Pde4 inhibitors, pharmaceutical compositions, and therapeutic applications

ABSTRACT

Provided herein are phosphodiesterase 4 (PDE4) inhibitors, e.g., a compound of Formula (I) or (II), and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a disease, disorder, or condition associated with PDE4 malfunction.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of the priority of U.S. ProvisionalApplication No. 62/947,421, filed Dec. 12, 2019; the disclosure of whichis incorporated herein by reference in its entirety.

FIELD

Provided herein are phosphodiesterase 4 (PDE4) inhibitors andpharmaceutical compositions thereof. Also provided herein are methods oftheir use for treating, preventing, or ameliorating one or more symptomsof a disease, disorder, or condition mediated by a PDE4.

BACKGROUND

Aberrant protein function or protein imbalance is a hallmark of manydisease states. For example, the functioning of the immune system isfinely balanced by the activities of pro-inflammatory andanti-inflammatory mediators or cytokines. Some cytokines promoteinflammation (pro-inflammatory cytokines), whereas other cytokinessuppress the activity of the pro-inflammatory cytokines(anti-inflammatory cytokines). For example, interleukin-4 (IL-4),interleukin-10 (IL-10), and interleukin-13 (IL-13) are potent activatorsof B lymphocytes, and also act as anti-inflammatory agents. They areanti-inflammatory cytokines by virtue of their ability to suppress genesfor pro-inflammatory cytokines, such as interleukin-1 (IL-1), a tumornecrosis factor (TNF), and chemokines.

Unregulated activities of these mediators can lead to the development ofserious inflammatory conditions. For example, autoimmune diseases arisewhen immune system cells (lymphocytes and macrophages) become sensitizedagainst the “self.” Lymphocytes as well as macrophages are usually undercontrol in this system. However, a misdirection of the system toward thebody's own tissues may happen in response to still unexplained triggers.One hypothesis is that lymphocytes recognize an antigen which mimics the“self” and a cascade of activation of different components of the immunesystem takes place, ultimately leading to tissue destruction. Geneticpredisposition has also been postulated to be responsible for autoimmunedisorders.

For example, a phosphodiesterase 4 (PDE4) is involved in the cytokineproduction of inflammatory cells, angiogenesis, and the functionalproperties of other cell types such as keratinocytes, in part, throughdegradation of cyclic adenosine monophosphate (cAMP). cAMP is animportant second messenger that regulates inflammatory responses.Accordingly, inhibitors of PDE4 may block the synthesis of severalpro-inflammatory cytokines and chemokines, such as tumor necrosis factoralpha (TNF-α), interleukin-23 (IL-23), chemokine ligand 9 (CXCL9, alsoknown as monokine induced by interferon gamma (MIG)), and chemokineligand 10 (CXCL10, also known as interferon gamma-induced protein 10(IP-10)) in multiple cell types, and may interfere with the productionof leukotriene B4, inducible nitric oxide synthase, and matrixmetalloproteinases. This interference reduces certain inflammatoryprocesses, such as dendritic cell infiltration, epidermal skinthickening, and joint destruction, for example, in psoriasis and otherinflammatory and/or autoimmune diseases such as arthritis, ankylosingspondylitis, osteoarthritis, rheumatoid arthritis, Behcet's disease,inflammatory bowel diseases (e.g., Crohn's disease and ulcerativecolitis), psoriasis, atopic dermatitis, and contact dermatitis.

Psoriasis is an autoimmune skin disease caused by pro-inflammatorycytokines, interferon gamma (IFN-7) and TNF-α. The psoriatic immuneresponse involves monocytes, dendritic cells, neutrophils and T cells,which all contribute to aberrant keratinocyte proliferation. PDE4inhibition may reduce production of multiple mediators, including TNF-α,IFN-γ, CXCL9, CXCL10, interleukin-2 (IL-2), interleukin-12 (IL-12),interleukin-23 (IL-23), macrophage inflammatory protein-1-alpha(MIP-1α), monocyte chemoattractant protein-1 (MCP1), and granulocytemacrophage-colony stimulating factor (GM-CSF) from PBMCs. Thus, there isa continued need for small molecule PDE4 inhibitors as an effectivetherapy for treating an inflammatory disease.

SUMMARY

Provided herein is a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R^(Het) is

-   -   each of X and X¹ is independently CH₂, C═O, SO, SO₂, or        CH₂C(═O);    -   each Y is independently H, deuterium, halogen, or optionally        substituted C₁-C₆ alkyl;    -   each R¹ is independently deuterium, hydroxyl, halogen, nitro,        cyano, —NR⁹R¹⁰, —NR⁹C(═O)R¹¹, —NR⁹SO₂R¹¹, —N(C(═O)R⁹)(C(═O)R¹¹),        optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆        alkoxy, optionally substituted C₃-C₇ cycloalkyl, optionally        substituted 3 to 10 membered heterocyclyl, optionally        substituted C₆-C₁₀ aryl, or optionally substituted 5 to 10        membered heteroaryl;    -   R² is hydroxyl, —NR⁹R¹⁰, optionally substituted C₁-C₆ alkyl,        optionally substituted C₃-C₇ cycloalkyl, optionally substituted        3 to 10 membered heterocyclyl, optionally substituted C₆-C₁₀        aryl, or optionally substituted 5 to 10 membered heteroaryl;    -   each of R³, R⁶, and R⁷ is independently H, deuterium, halogen,        optionally substituted C₁-C₆ alkyl, C₁-C₆ haloalkyl, optionally        substituted C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, optionally        substituted C₃-C₇ cycloalkyl, optionally substituted 3 to 10        membered heterocyclyl, optionally substituted C₆-C₁₀ aryl, or        optionally substituted 5 to 10 membered heteroaryl;    -   each of R⁴ and R⁵ is independently optionally substituted C₁-C₆        alkyl, optionally substituted C₃-C₇ cycloalkyl, optionally        substituted (C₃-C₇ cycloalkyl)C₁-C₆ alkyl, optionally        substituted 3 to 10 membered heterocyclyl, optionally        substituted (3 to 10 membered heterocyclyl)C₁-C₆ alkyl,        optionally substituted C₆-C₁₀ aryl, optionally substituted        C₇-C₁₄ aralkyl, optionally substituted 5 to 10 membered        heteroaryl, or (optionally substituted 5 to 10 membered        heteroaryl)C₁-C₆ alkyl;    -   R⁸ is H or deuterium;    -   each of R⁹ and R¹⁰ is independently H, optionally substituted        C₁-C₆ alkyl, C₁-C₆ haloalkyl, (C₁-C₆ alkoxy)C₁-C₆ alkyl,        optionally substituted C₃-C₇ cycloalkyl, optionally substituted        3 to 10 membered heterocyclyl, optionally substituted C₆-C₁₀        aryl, optionally substituted C₇-C₁₄ aralkyl, or optionally        substituted 5 to 10 membered heteroaryl; and    -   R¹¹ is optionally substituted C₁-C₆ alkyl, C₁-C₆ haloalkyl,        (C₁-C₆ alkoxy)C₁-C₆ alkyl, optionally substituted C₃-C₇        cycloalkyl, optionally substituted (C₃-C₇ cycloalkyl)C₁-C₆        alkyl, optionally substituted 3 to 10 membered heterocyclyl,        optionally substituted (3 to 10 membered heterocyclyl)C₁-C₆        alkyl, optionally substituted C₆-C₁₀ aryl, optionally        substituted C₇-C₁₄ aralkyl, optionally substituted 5 to 10        membered heteroaryl, or (optionally substituted 5 to 10 membered        heteroaryl)C₁-C₆ alkyl;    -   provided that at least one of R², R⁴, and R⁵ is optionally        substituted C₃-C₇ cycloalkyl.

Also provided herein is a compound of Formula (II):

R^(W)-L²-X-L¹-R¹  (II)

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R¹ is

-   -   X is C₁-C₁₅ alkylene, heteroalkylene, C₂-C₁₀ alkenylene, C₂-C₁₀        alkynylene, phenylene, five to six membered heteroarylene, five        to six membered heterocyclylene, or C₃-C₈ cycloalkylene, wherein        each of phenylene, five to six membered heteroarylene, five to        six membered heterocyclylene, or C₃-C₈ cycloalkylene is        optionally substituted with one or more R¹⁸; or X is C₁-C₁₅        alkylene, heteroalkylene, C₂-C₁₀ alkenylene, or C₂-C₁₀        alkynylene, wherein one or more methylene repeating units is        replaced by a ring structure selected from the group consisting        of phenylene, five to six membered heteroarylene, five to six        membered heterocyclylene, or C₃-C₈ cycloalkylene, and wherein        each ring structure is optionally substituted with one or more        R¹⁸;    -   each Y is independently CH₂, O, S, or NH;    -   L¹ is a bond,

-   -   L² is a bond, —O—, —S—, —NR^(16a)—, —(CH₂)₁₋₃—, —C(═O)—, or        —(CH₂)₀₋₃C(═O)NR^(16a)—;    -   each Q is independently CH₂ or C(═O);    -   each of Q¹, Q², and Q³ is independently S or CH, provided that        one of Q¹, Q², and Q³ is S;    -   each R^(A) is independently deuterium, hydroxyl, halogen, cyano,        nitro, optionally substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,        optionally substituted amino, C₁-C₆ alkylamino, (amino)C₁-C₆        alkyl, —(C═O)NR^(17a)R^(17b), (C₁-C₆ alkoxy)C₁-C₆ alkyl,        —O—(C₁-C₆ alkoxy)C₁-C₆ alkyl, or optionally substituted C₃-C₇        cycloalkyl;    -   each of R², R^(2a) and R^(2b) is independently H, deuterium,        halogen, or C₁-C₆ alkyl;    -   each R^(2c) is independently H, C₁-C₆ alkyl, or C₃-C₈        cycloalkyl, wherein the C₃-C₈ cycloalkyl is optionally        substituted with C₁-C₆ alkyl, halogen, or C₁-C₆ haloalkyl;    -   each R^(2d) is independently H, OH, halogen, —O—C₁-C₆ alkyl,        —O—C₁-C₆ haloalkyl, or —O—C₃-C₈ cycloalkyl, wherein —O—C₃-C₈        cycloalkyl is optionally substituted with C₁-C₆ alkyl, halogen,        or C₁-C₆ haloalkyl;    -   each R^(2e) is independently —C(═O)—C₁-C₆ alkyl or —C(═O)—C₃-C₈        cycloalkyl, each optionally substituted with one or more        substituents, each of which is independently selected from the        group consisting of cyano, halogen, hydroxyl, amino, and C₁-C₆        haloalkyl;    -   each R³ is independently H, deuterium, C₁-C₆ alkyl,

-   -   each R⁴ is independently —NR^(4A)R^(4B), —NR^(4A)C(═O)R^(4C),        —NR^(4A)SO₂R^(4C), or —N(C(═O)R^(4A))(C(═O)R^(4C)).    -   each of R^(4A) and R^(4B) is independently H, optionally        substituted C₁-C₆ alkyl, C₁-C₆ haloalkyl, (C₁-C₆ alkoxy)C₁-C₆        alkyl, optionally substituted C₃-C₇ cycloalkyl, optionally        substituted 3 to 10 membered heterocyclyl, optionally        substituted C₆-C₁₀ aryl, optionally substituted C₇-C₁₄ aralkyl,        or optionally substituted 5 to 10 membered heteroaryl;    -   each R^(4C) is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl,        (C₁-C₆ alkoxy)C₁-C₆ alkyl, optionally substituted C₃-C₇        cycloalkyl, optionally substituted (C₃-C₇ cycloalkyl)C₁-C₆        alkyl, optionally substituted 3 to 10 membered heterocyclyl,        optionally substituted (3 to 10 membered heterocyclyl)C₁-C₆        alkyl, optionally substituted C₆-C₁₀ aryl, optionally        substituted C₇-C₁₄ aralkyl, optionally substituted 5 to 10        membered heteroaryl, or (optionally substituted 5 to 10 membered        heteroaryl)C₁-C₆ alkyl;    -   each R⁵ is independently H, deuterium, halogen, or optionally        substituted C₁-C₆ alkyl;    -   each R⁶ is independently hydroxyl, —NR^(4A)R^(4B), C₁-C₆ alkyl,        optionally substituted C₃-C₇ cycloalkyl, optionally substituted        3 to 10 membered heterocyclyl, optionally substituted C₆-C₁₀        aryl, or optionally substituted 5 to 10 membered heteroaryl;    -   each of R⁷, R¹⁰, and R¹¹ is independently H, deuterium, halogen,        C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,        optionally substituted C₃-C₇ cycloalkyl, optionally substituted        3 to 10 membered heterocyclyl, optionally substituted C₆-C₁₀        aryl, or optionally substituted 5 to 10 membered heteroaryl;    -   each of R⁸ and R⁹ is independently optionally substituted C₁-C₆        alkyl, C₁-C₆ haloalkyl, optionally substituted C₃-C₇ cycloalkyl,        optionally substituted (C₃-C₇ cycloalkyl)C₁-C₆ alkyl, optionally        substituted 3 to 10 membered heterocyclyl, optionally        substituted (3 to 10 membered heterocyclyl)C₁-C₆ alkyl,        optionally substituted C₆-C₁₀ aryl, optionally substituted        C₇-C₁₄ aralkyl, optionally substituted 5 to 10 membered        heteroaryl, or (optionally substituted 5 to 10 membered        heteroaryl)C₁-C₆ alkyl;    -   each R¹² is independently H or deuterium;    -   each of R¹³ and R¹⁴ is independently halogen, hydroxyl, cyano,        nitro, optionally substituted C₁-C₆ alkyl, C₁-C₆ haloalkyl,        C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, optionally substituted amino,        (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O—(C₁-C₆ alkoxy)C₁-C₆ alkyl, or        optionally substituted C₃-C₇ cycloalkyl;    -   each of R¹⁵, R¹⁶, R^(16a), and R^(16b) is independently H or        C₁-C₆ alkyl;    -   each R^(17a) and R^(17b) is independently H or C₁-C₆ alkyl, or        R^(17a) and R^(17b) together with the nitrogen atom to which        they are attached form 5 or 6 membered heterocyclyl, each        optionally substituted with one or more R¹⁸;    -   each R¹⁸ is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆        haloalkyl, C₁-C₆ haloalkoxy, (C₁-C₆ alkoxy)C₁-C₆ alkyl,        —O—(C₁-C₆ alkoxy)C₁-C₆ alkyl, optionally substituted amino,        halogen, or cyano; or two geminal R¹⁸ form oxo;    -   each of R^(19a) and R^(19b) is independently H, optionally        substituted C₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl,        optionally substituted C₂-C₆ alkynyl, optionally substituted        C₆-C₁₀ aryl, optionally substituted 5 to 10 membered heteroaryl,        optionally substituted C₇-C₁₄ aralkyl, optionally substituted 3        to 10 membered heterocyclyl, or optionally substituted C₃-C₈        carbocyclyl;    -   each of R^(20a) and R^(20b) is independently H, halogen, C₁-C₆        alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or C₃-C₈        carbocyclyl;    -   each of R^(21a) and R^(21b) is independently H, optionally        substituted C₁-C₆ alkyl, optionally substituted C₆-C₁₀ aryl,        optionally substituted C₇-C₁₄ aralkyl, or optionally substituted        C₃-C₈ carbocyclyl;    -   each of X¹ and X² is independently O or S;    -   each Z¹ is independently a bond, —(CR^(a)R^(b))_(q1)—, —C(═O)—,        —CH═CH—, or —C≡C—;    -   each Z² is independently —(CR^(c)R^(d))_(q2)—;    -   each of Z³ and Z⁴ is independently NR¹⁶, O, S, or a bond;    -   each of R^(a), R^(b), R^(c), and R^(d) is independently H,        halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,        C₁-C₆ haloalkoxy, or optionally substituted C₃-C₆ cycloalkyl;    -   each Ring A is independently phenylene, five to six membered        heteroarylene, five to six membered heterocyclylene, or C₃-C₈        cycloalkylene, each optionally substituted with one or more R¹⁸;    -   each of m1, m2, m3, m4, m5, m6, m7, m8, m9, k1, k2, k3, k4, k5,        k6, k7, k8, and k9 is independently an integer of 0, 1, 2, 3, 4,        or 5;    -   each n is independently an integer of 0, 1, or 2; and    -   each q1 and q2 is independently an integer of 1, 2, or 3.

Additionally, provided herein is a pharmaceutical composition comprisinga compound of Formula (I) or (II), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable excipient.

Furthermore, provided herein is a method of treating, preventing, orameliorating one or more symptoms of a disease, disorder, or conditionassociated with a PDE4 in a subject, comprising administering to thesubject in need thereof a therapeutically effective amount of a compoundof Formula (I) or (II), or a pharmaceutically acceptable salt thereof.

Provided herein is a method of treating, preventing, or ameliorating oneor more symptoms of an inflammatory disease in a subject, comprisingadministering to the subject in need thereof a therapeutically effectiveamount of a compound of Formula (I) or (II), or a pharmaceuticallyacceptable salt thereof.

Provided herein is a method of treating, preventing, or ameliorating oneor more symptoms of psoriasis, psoriatic arthritis, or atopic dermatitisin a subject, comprising administering to the subject in need thereof atherapeutically effective amount of a compound of Formula (I) or (II),or a pharmaceutically acceptable salt thereof.

Provided herein is a method of inhibiting the activity of aphosphodiesterase 4 (PDE4), comprising contacting the PDE4 with aneffective amount of a compound of Formula (I) or (II), or apharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as are commonly understood by one of ordinaryskill in the art. In the event that there are a plurality of definitionsfor a term herein, those in this section prevail unless statedotherwise. As used in the specification and the appended claims, thesingular forms “a,” “an,” and “the” include plural referents unless thecontext clearly dictates otherwise. Unless otherwise indicated,conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry,biochemistry, recombinant DNA techniques, and pharmacology are employed.The use of “or” or “and” means “and/or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as“include,” “includes,” and “included,” is not limiting.

Unless otherwise defined, all terms (including technical and scientificterms) are to be given their ordinary and customary meaning to a personof ordinary skill in the art and are not to be limited to a special orcustomized meaning unless expressly so defined herein. It should benoted that the use of particular terminology when describing certainfeatures or aspects of the disclosure should not be taken to imply thatthe terminology is being re-defined herein to be restricted to includeany specific characteristics of the features or aspects of thedisclosure with which that terminology is associated.

Where a range of values is provided, it is understood that the upper andlower limit, and each intervening value between the upper and lowerlimit of the range is encompassed within the embodiments.

As used herein, any “R” group(s) represent substituents that can beattached to the indicated atom. An R group may be substituted orunsubstituted. If two “R” groups are described as being “takentogether,” the R groups and the atoms they are attached to can formcycloalkyl, aryl, heteroaryl, or heterocyclyl. For example, withoutlimitation, if R^(a) and R^(b), and the atom to which they are attached,are indicated to be “taken together” or “joined together,” it means thatthey are covalently bonded to one another to form a ring.

Whenever a group is described as being “optionally substituted,” thatgroup may be unsubstituted or substituted with one or more of thesubstituents specified. Likewise, when a group is described as being“substituted,” the substituent may be selected from one or more of thesubstituents specified. If no substituents are specified, it is meantthat the “optionally substituted” or “substituted” group may besubstituted with one or more groups, each of which is individually andindependently alkyl (e.g., C₁-C₆ alkyl); alkenyl (e.g., C₂-C₆ alkenyl);alkynyl (e.g., C₂-C₆ alkynyl); C₃-C₈ carbocyclyl (e.g., C₃-C₈cycloalkyl, C₃-C₈ cycloalkenyl, or C₃-C₈ cycloalkynyl, each furtheroptionally substituted, for example, with halo, C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, (C₁-C₆ alkoxy)C₁-C₆ alkyl, or—O(C₁-C₆ alkoxy)C₁-C₆ alkyl); (C₃-C₇ carbocyclyl)C₁-C₆ alkyl (furtheroptionally substituted, for example, with halo, C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, (C₁-C₆ alkoxy)C₁-C₆ alkyl, or—O(C₁-C₆ alkoxy)C₁-C₆ alkyl); 5-10 membered heterocyclyl (furtheroptionally substituted, for example, with halo, C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, (C₁-C₆ alkoxy)C₁-C₆ alkyl, or—O(C₁-C₆ alkoxy)C₁-C₆ alkyl); (5-10 membered heterocyclyl)C₁-C₆ alkyl(further optionally substituted, for example, with halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, (C₁-C₆ alkoxy)C₁-C₆alkyl, or —O(C₁-C₆ alkoxy)C₁-C₆ alkyl); aryl (further optionallysubstituted, for example, with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, (C₁-C₆ alkoxy)C₁-C₆ alkyl, or —O(C₁-C₆alkoxy)C₁-C₆ alkyl); (aryl)C₁-C₆ alkyl (further optionally substituted,for example, with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, (C₁-C₆ alkoxy)C₁-C₆ alkyl, or —O(C₁-C₆ alkoxy)C₁-C₆alkyl); 5-10 membered heteroaryl (further optionally substituted withhalo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,(C₁-C₆ alkoxy)C₁-C₆ alkyl, or —O(C₁-C₆ alkoxy)C₁-C₆ alkyl); (5-10membered heteroaryl)C₁-C₆ alkyl (further optionally substituted withhalo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,(C₁-C₆ alkoxy)C₁-C₆ alkyl, or —O(C₁-C₆ alkoxy)C₁-C₆ alkyl); halo (e.g.,fluoro, chloro, bromo, or iodo); cyano; hydroxyl; protected hydroxyl;alkoxy (e.g., C₁-C₆ alkoxy); haloalkyl (e.g., C₁-C₆ haloalkyl, such as—CF₃); haloalkyl (e.g., C₁-C₆ haloalkoxy, such as —OCF₃); (C₁-C₆alkoxy)C₁-C₆ alkyl; —O(C₁-C₆ alkoxy)C₁-C₆ alkyl; (C₁-C₆ haloalkoxy)C₁-C₆alkyl; —O(C₁-C₆ haloalkoxy)C₁-C₆ alkyl; aryloxy; sulfhydryl (mercapto);alkylthio (e.g., C₁-C₆ alkylthio); arylthio; azido; nitro; O-carbamyl;N-carbamyl; O-thiocarbamyl; N-thiocarbamyl; C-amido; N-amido;S-sulfonamido; N-sulfonamido; C-carboxy; protected C-carboxy; O-carboxy;acyl; cyanate; isocyanato; thiocyanato; isothiocyanato; silyl; sulfenyl;sulfinyl; sulfonyl; trihalomethanesulfonyl; trihalomethanesulfonamido;amino; mono-substituted amino (e.g., NH(C₁-C₆ alkyl); di-substitutedamino (e.g., N(C₁-C₆ alkyl)₂); oxo (═O); or thioxo (═S).

As used herein, the term “C_(a) to C_(b),” in which “a” and “b” are eachan integer, refers to, for example, the number of carbon atoms in analkyl, alkenyl, or alkynyl group, or the number of ring atoms of acycloalkyl, aryl, heteroaryl, or heterocyclyl group. That is, the alkyl,the ring of the cycloalkyl, or the ring of the aryl, contains from “a”to “b,” inclusive, carbon atoms. Likewise, the ring of the heteroaryl orthe ring of the heterocyclyl contains from “a” to “b,” inclusive, totalring atoms. Thus, for example, a “C₁ to C₄ alkyl” group refers to allalkyl groups having from 1 to 4 carbons, e.g., —CH₃, —CH₂CH₃,—CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH(CH₃)CH₂CH₃, and —C(CH₃)₃; a C₃to C₄ cycloalkyl group refers to all cycloalkyl groups having from 3 to4 carbon atoms, e.g., cyclopropyl and cyclobutyl. Similarly, a “4 to 6membered heterocyclyl” group refers to all heterocyclyl groups with 4 to6 total ring atoms, e.g., azetidinyl, oxetanyl, oxazolinyl,pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl. If no “a” and“b” are designated with regard to an alkyl, cycloalkyl, aryl,heteroaryl, or heterocyclyl group, the broadest range described in thesedefinitions is to be assumed. As used herein, the term “C₁-C₆” includesC₁, C₂, C₃, C₄, C₅, and C₆, and a range defined by any of the twonumbers. For example, C₁-C₆ alkyl includes C₁, C₂, C₃, C₄, C₅, and C₆alkyl, C₂-C₆ alkyl, C₁-C₃ alkyl, etc. Similarly, C₃-C₈ carbocyclyl orcycloalkyl each includes hydrocarbon ring containing 3, 4, 5, 6, 7, and8 carbon atoms, or a range defined by any of the two numbers, such asC₃-C₇ cycloalkyl or C₅-C₆ cycloalkyl.

As used herein, “alkyl” refers to a straight or branched hydrocarbonchain that comprises a fully saturated (no double or triple bonds)hydrocarbon group. The alkyl group can have 1 to 20 carbon atoms(whenever it appears herein, a numerical range such as “1 to 20” refersto each integer in the given range; e.g., “1 to 20 carbon atoms” meansthat the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3carbon atoms, etc., up to and including 20 carbon atoms, although thepresent definition also covers the occurrence of the term “alkyl” whereno numerical range is designated). The alkyl group can be a medium sizealkyl having 1 to 10 carbon atoms. The alkyl group can be a lower alkylhaving 1 to 6 carbon atoms. By way of example only, “C₁-C₄ alkyl”indicates that there are one to four carbon atoms in the alkyl chain,i.e., the alkyl chain is selected from methyl, ethyl, propyl, isopropyl,n-butyl, isobutyl, sec-butyl, and t-butyl. Exemplary alkyl groupsinclude, but are not limited to, methyl, ethyl, n-propyl, isopropyl,butyl, isobutyl, tertiary butyl, pentyl (straight chain or branched),and hexyl (straight chain or branched). The alkyl group can besubstituted or unsubstituted.

As used herein, “alkenyl” refers to a straight or branched hydrocarbonchain containing one or more double bonds. The alkenyl group can have 2to 20 carbon atoms. By way of example only, “C₂-C₆ alkenyl” indicatesthat there are two to six carbon atoms in the alkenyl chain, e.g., thealkenyl chain is selected from the group consisting of ethenyl,propen-1-yl, propen-2-yl, propen-3-yl, buten-1-yl, buten-2-yl,buten-3-yl, buten-4-yl, 1-methyl-propen-1-yl, 2-methyl-propen-1-yl,1-ethyl-ethen-1-yl, 2-methyl-propen-3-yl, buta-1,3-dienyl,buta-1,2-dienyl, and buta-1,2-dien-4-yl. Exemplary alkenyl groupsinclude, but are not limited to, ethenyl, propenyl, butenyl, pentenyl,and hexenyl. The alkenyl group can be substituted or unsubstituted.

As used herein, “alkynyl” refers to a straight or branched hydrocarbonchain containing one or more triple bonds. The alkynyl group can have 2to 20 carbon atoms. By way of example only, “C₂-C₆ alkynyl” indicatesthat there are two to six carbon atoms in the alkynyl chain, e.g., thealkynyl chain is selected from the group consisting of ethynyl,propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-3-yl, butyn-4-yl, and2-butynyl. Exemplary alkynyl groups include, but are not limited to,ethynyl, propynyl, butynyl, pentynyl, and hexynyl. The alkynyl group canbe substituted or unsubstituted.

As used herein, “cycloalkyl” refers to a completely saturated (no doubleor triple bonds) mono- or multi-cyclic hydrocarbon ring system. Whencomposed of two or more rings, the rings may be joined together in afused, bridged, or spiro fashion. As used herein, the term “fused”refers to two rings that have two atoms and one bond in common. As usedherein, the term “bridged” refers to a cycloalkyl that contains alinkage of one or more atoms connecting non-adjacent atoms. As usedherein, the term “spiro” refers to two rings that have one atom incommon and the two rings are not linked by a bridge. A cycloalkyl groupcan contain 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s),or 3 to 6 atoms in the ring(s). A cycloalkyl group can be unsubstitutedor substituted. Examples of monocyclic cycloalkyl groups include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. Examples of bicyclic fused cycloalkylgroups include, but are not limited to, decahydronaphthalenyl,dodecahydro-1H-phenalenyl, and tetradecahydroanthracenyl. Examples ofbicyclic bridged cycloalkyl groups include, but are not limited to,bicyclo[1.1.1]pentyl, adamantanyl, and norbornenyl. Examples of bicyclicspiro cycloalkyl groups include, but are not limited to,spiro[3.3]heptanyl and spiro[4.5]decanyl.

As used herein, “carbocyclyl” refers to a non-aromatic mono- ormulti-cyclic hydrocarbon ring system. When composed of two or morerings, the rings may be joined together in a fused, bridged, or spirofashion. A carbocyclyl group can contain 3 to 30 atoms in the ring(s), 3to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atomsin the ring(s), or 3 to 6 atoms in the ring(s). A carbocyclyl group canbe unsubstituted or substituted. Examples of carbocyclyl groups include,but are not limited to, cycloalkyl groups, and the non-aromatic portionsof 1,2,3,4-tetrahydronaphthyl, 2,3-dihydro-1H-indenyl,5,6,7,8-tetrahydroquinolinyl, and 6,7-dihydro-5H-cyclopenta[b]pyridinyl.

As used herein, “aryl” refers to a carbocyclic (all carbon) monocyclicor multicyclic aromatic ring system (including fused ring systems wheretwo carbocyclic rings share a chemical bond). For example, the arylgroup can be a C₆ aryl group or a C₁₀ aryl group. Examples of arylgroups include, but are not limited to, phenyl and naphthyl. An arylgroup can be substituted or unsubstituted.

As used herein, “heteroaryl” refers to a monocyclic or multicyclicaromatic ring system (a ring system with fully delocalized pi-electronsystem) that contain(s) one or more heteroatoms (for example, 1, 2, or 3heteroatoms), that is, an element other than carbon, including, but notlimited to, nitrogen, oxygen, and sulfur. For example, the heteroarylgroup can contain 5 to 10 atoms in the ring(s), 6 to 10 atoms in thering(s), or 5 to 6 atoms in the ring(s); such as nine carbon atoms andone heteroatom; eight carbon atoms and two heteroatoms; seven carbonatoms and three heteroatoms; eight carbon atoms and one heteroatom;seven carbon atoms and two heteroatoms; six carbon atoms and threeheteroatoms; five carbon atoms and four heteroatoms; five carbon atomsand one heteroatom; four carbon atoms and two heteroatoms; three carbonatoms and three heteroatoms; four carbon atoms and one heteroatom; threecarbon atoms and two heteroatoms; or two carbon atoms and threeheteroatoms. Furthermore, the term “heteroaryl” includes fused ringsystems, where two rings, such as at least one aryl ring and at leastone heteroaryl ring, or at least two heteroaryl rings, share at leastone chemical bond. Examples of heteroaryl rings include, but are notlimited to, furanyl, furazanyl, thiophenyl, benzothiophenyl,phthalazinyl, pyrrolyl, oxazolyl, benzoxazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,benzothiazolyl, imidazolyl, benzimidazolyl, indolyl, indazolyl,pyrazolyl, benzopyrazolyl, isoxazolyl, benzoisoxazolyl, isothiazolyl,triazolyl, benzotriazolyl, thiadiazolyl, tetrazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, purinyl, pteridinyl, quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, and triazinyl. Aheteroaryl group can be substituted or unsubstituted.

As used herein, “heterocyclyl” refers to a three-, four-, five-, six-,seven-, eight-, nine-, or ten-membered monocyclic, bicyclic, ortricyclic ring system, wherein carbon atoms together with from 1 to 5heteroatoms constitute the ring system. A heterocyclyl group mayoptionally contain one or more unsaturated bonds situated in such a way,however, that a fully delocalized pi-electron system does not occurthroughout all the rings (i.e., heterocyclyl groups are not aromatic).The heteroatom(s) is an element other than carbon, including, but notlimited to, oxygen, sulfur, and nitrogen. A heterocyclyl group canfurther contain one or more carbonyl functionalities so as to make thedefinition to include oxo-systems such as lactams, lactones, and cycliccarbamates. When composed of two or more rings, the rings can be joinedtogether in a fused, bridged, or spiro fashion. As used herein, the term“fused” refers to two rings that have two atoms and one bond in common.As used herein, the term “bridged heterocyclyl” refers to a heterocyclylthat contains a linkage of one or more atoms connecting non-adjacentatoms. As used herein, the term “spiro” refers to two rings that haveone atom in common and the two rings are not linked by a bridge. Aheterocyclyl group can contain 3 to 10 atoms in the ring(s), 3 to 8atoms in the ring(s), 3 to 6 atoms in the ring(s), or 5 to 6 atoms inthe ring(s); for example, five carbon atoms and one heteroatom; fourcarbon atoms and two heteroatoms; three carbon atoms and threeheteroatoms; four carbon atoms and one heteroatom; three carbon atomsand two heteroatoms; two carbon atoms and three heteroatoms; one carbonatom and four heteroatoms; three carbon atoms and one heteroatom; or twocarbon atoms and one heteroatom. Additionally, any nitrogen in aheterocyclyl group can be quaternized. A heterocyclyl group can belinked to the rest of a molecule via a carbon atom in the heterocyclylgroup (C-linked) or via a heteroatom in the heterocyclyl group, such asa nitrogen atom (N-linked). Heterocyclyl groups can be unsubstituted orsubstituted. Examples of heterocyclyl groups include, but are notlimited to, aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl,1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,2-dioxolanyl,1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-oxathianyl, 1,4-oxathiinyl,1,3-oxathiolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, 1,4-oxathianyl,tetrahydro-1,4-thiazinyl, 2H-1,2-oxazinyl, maleimidyl, succinimidyl,barbituryl, thiobarbituryl, dioxopiperazinyl, hydantoinyl,dihydrouracyl, trioxanyl, hexahydro-1,3,5-triazinyl, imidazolinyl,imidazolidinyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl,oxazolidinonyl, thiazolinyl, thiazolidinyl, morpholinyl, oxiranyl,N-oxypiperidinyl, piperidinyl, piperazinyl, pyrrolidinyl, azepanyl,pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl,2-oxopyrrolidinyl, tetrahydropyranyl, 4H-pyranyl, tetrahydrothiopyranyl,thiamorpholinyl, benzimidazolidinonyl, tetrahydroquinolinyl, and3,4-methylenedioxyphenyl. Examples of spiro heterocyclyl groups include,but are not limited to, 2-azaspiro[3.3]heptanyl,2-oxaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl,2,6-diazaspiro[3.3]heptanyl, 2-oxaspiro[3.4]octanyl, and2-azaspiro[3.4]octanyl.

As used herein, “alkylene” refers to a branched or straight chain fullysaturated di-radical hydrocarbon group, which is attached to the rest ofa molecule via two points of attachment. By way of example only, “C₁-C₁₀alkylene” indicates that there are one to ten carbon atoms in thealkylene chain. Non-limiting examples include ethylene (—CH₂CH₂—),propylene (—CH₂CH₂CH₂—), butylene (—CH₂CH₂CH₂CH₂—), and pentylene(—CH₂CH₂CH₂CH₂CH₂—).

As used herein, “alkenylene” refers to a straight or branched chaindi-radical hydrocarbon group containing at least one carbon-carbondouble bond, which is attached to the rest of a molecule via two pointsof attachment. By way of example only, “C₂-C₁₀ alkenylene” indicatesthat there are two to ten carbon atoms in the alkenylene chain.

As used herein, “alkynylene” refers to a straight or branched chaindi-radical hydrocarbon group containing at least one carbon-carbontriple bond, which is attached to the rest of a molecule via two pointsof attachment. By way of example only, “C₂-C₁₀ alkynylene” indicatesthat there are two to ten carbon atoms in the alkynylene chain.

As used herein, “heteroalkylene” refers to an alkylene group as definedherein that contains one or more heteroatoms in the carbon backbone(i.e., an alkylene group in which one or more carbon atoms is replacedwith a heteroatom, for example, a nitrogen atom, oxygen atom, or sulfuratom). Heteroalkylene groups include, but are not limited to, ether,thioether, amino-alkylene, and alkylene-amino-alkylene moieties.

As used herein, “aralkyl” and “(aryl)alkyl” refer to an aryl group asdefined herein, connected, as a substituent, via an alkylene group asdefined herein. The alkylene and aryl groups of an aralkyl can each beindependently substituted or unsubstituted. Examples include, but arenot limited to, benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl.

As used herein, “heteroaralkyl” and “(heteroaryl)alkyl” refer to aheteroaryl group as defined herein, connected, as a substituent, via analkylene group as defined herein. The alkylene and heteroaryl groups ofheteroaralkyl can each be independently substituted or unsubstituted.Examples include, but are not limited to 2-thienylalkyl, 3-thienylalkyl,furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl,and imidazolylalkyl.

As used herein, “(heterocyclyl)alkyl” refer to a heterocyclic orheterocyclyl group as defined herein, connected, as a substituent, viaan alkylene group as defined herein. The alkylene and heterocyclylgroups of (heterocyclyl)alkyl can each be independently substituted orunsubstituted. Examples include, but are not limited to,(tetrahydro-2H-pyran-4-yl)methyl, (piperidin-4-yl)ethyl,(piperidin-4-yl)propyl, (tetrahydro-2H-thiopyran-4-yl)methyl, and(1,3-thiazinan-4-yl)methyl.

As used herein, “cycloalkylalkyl” and “(cycloalkyl)alkyl” refer to acycloalkyl group as defined herein, connected, as a substituent, via analkylene group. The alkylene and cycloalkyl groups of (cycloalkyl)alkylcan each be independently substituted or unsubstituted. Examplesinclude, but are not limited to, cyclopropylmethyl, cyclobutylmethyl,cyclopentylethyl, and cyclohexylpropyl.

As used herein, “alkoxy” refers to the formula —OR, wherein R is analkyl group as defined herein. Examples include, but are not limited to,methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy,isobutoxy, sec-butoxy, and tert-butoxy. An alkoxy can be substituted orunsubstituted.

As used herein, “haloalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by a halogen (e.g.,mono-haloalkyl, di-haloalkyl, and tri-haloalkyl). Examples include, butare not limited to, chloromethyl, fluoromethyl, difluoromethyl,trifluoromethyl, 1-chloro-2-fluoromethyl, and 2-fluoroisobutyl. Ahaloalkyl can be substituted or unsubstituted.

As used herein, “haloalkoxy” refers to an alkoxy group in which one ormore of the hydrogen atoms are replaced by a halogen (e.g.,mono-haloalkoxy, di-haloalkoxy, and tri-haloalkoxy). Examples include,but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy,trifluoromethoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy. Ahaloalkoxy can be substituted or unsubstituted.

As used herein, “amino” refer to an —NH₂ group. The term“mono-substituted amino group” as used herein refers to an amino (—NH₂)group, where one of the hydrogen atom is replaced by a substituent. Theterm “di-substituted amino group” as used herein refers to an amino(—NH₂) group, where each of the two hydrogen atoms is independentlyreplaced by a substituent. The term “optionally substituted amino” asused herein refer to an —NR_(A)R_(B) group, where R_(A) and R_(B) areeach independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl,heterocyclyl, aralkyl, or heterocyclyl(alkyl), each as defined herein.

As used herein, “alkylamino” or “(alkyl)amino” refers to a —NR_(A)R_(B)group, where R_(A) is hydrogen or alkyl and R_(B) is alkyl. Examples ofalkylamino groups include, but are not limited to, methylamino (—NHMe),ethylamino (—NHEt), dimethylamino (—N(Me)₂), methylethylamino(—N(Me)(Et)), and isopropylamino (—NHiPr).

As used herein, “aminoalkyl” or “(amino)alkyl” refers to an alkyl groupin which one or more of the hydrogen atoms are replaced by an aminogroup or “—NR_(A)R_(B)” group as defined herein. Examples of aminoalkylgroups include, but are not limited to, —(CH₂)₁₋₄NH₂, —(CH₂)₁₋₄—NHCH₃,—(CH₂)₁₋₄—NHC₂H₅, —(CH₂)₁₋₄—N(CH₃)₂, —(CH₂)₁₋₄—N(C₂H₅)₂,—(CH₂)₁₋₄—NH—CH(CH₃)₂, —(CH₂)₁₋₄N(CH₃)C₂H₅, and —CH(NH₂)CH₃.

The term “halogen atom” or “halogen” as used herein refers to fluorine,chlorine, bromine, or iodine.

As used herein, “alkoxyalkyl” or “(alkoxy)alkyl” refers to an alkoxygroup connected via an alkylene group, such as C₂-C₈ alkoxyalkyl or(C₁-C₆ alkoxy)C₁-C₆ alkyl, for example, —(CH₂)₁₋₃—OCH₃.

As used herein, “—O-alkoxyalkyl” or “—O-(alkoxy)alkyl” refers to analkoxy group connected via an —O-(alkylene) group, such as —O—(C₁-C₆alkoxy)C₁-C₆ alkyl, for example, —O—(CH₂)₁₋₃—OCH₃.

As used herein, “aryloxy” and “arylthio” refers to —OR and —SR,respectively, wherein R is an aryl as defined herein, e.g., phenyl. Anaryloxy and arylthio can each be independently substituted orunsubstituted.

A “sulfenyl” group refers to an “—SR” group in which R is hydrogen,alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl, heterocyclyl,aralkyl, or heterocyclyl(alkyl), each as defined herein. A sulfenyl canbe substituted or unsubstituted.

A “sulfinyl” group refers to an “—S(═O)R” group in which R is hydrogen,alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl, heterocyclyl,aralkyl, or heterocyclyl(alkyl), each as defined herein. A sulfinyl canbe substituted or unsubstituted.

A “sulfonyl” group refers to an “—SO₂R” group in which R is hydrogen,alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl, heterocyclyl,aralkyl, or heterocyclyl(alkyl), each as defined herein. A sulfonyl canbe substituted or unsubstituted.

An “O-carboxy” group refers to an “—OC(═O)R” group in which R ishydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl,heterocyclyl, aralkyl, or heterocyclyl(alkyl), each as defined herein.An O-carboxy can be substituted or unsubstituted.

The terms “ester” and “C-carboxy” refer to a “—C(═O)OR” group in which Ris hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl,heterocyclyl, aralkyl, or heterocyclyl(alkyl), each as defined herein.An ester or C-carboxy can be substituted or unsubstituted.

A “trihalomethanesulfonyl” group refers to an “—O₂SCX′₃ “group, whereinX′ is a halogen.

A “trihalomethanesulfonamido” group refers to an “—N(R)S(O)₂CX′₃” group,wherein X′ is a halogen and R is hydrogen, alkyl, alkenyl, alkynyl,carbocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, orheterocyclyl(alkyl), each as defined herein.

A “mercapto” group refers to an “—SH” group.

An “S-sulfonamido” group refers to an “—SO₂N(R_(A)R_(B))” group in whichR_(A) and R_(B) can each be independently hydrogen, alkyl, alkenyl,alkynyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, orheterocyclyl(alkyl), each as defined herein. An S-sulfonamido can besubstituted or unsubstituted.

An “N-sulfonamido” group refers to an “—N(R_(A))SO₂R” group in which Rand R_(A) can each be independently hydrogen, alkyl, alkenyl, alkynyl,carbocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, orheterocyclyl(alkyl), each as defined herein. An N-sulfonamido can besubstituted or unsubstituted.

An “O-carbamyl” group refers to an “—OC(═O)N(R_(A)R_(B))” group in whichR_(A) and R_(B) can each be independently hydrogen, alkyl, alkenyl,alkynyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, orheterocyclyl(alkyl), each as defined herein. An O-carbamyl can besubstituted or unsubstituted.

An “N-carbamyl” group refers to an “—N(R_(A))C(═O)OR” group in which Rand R_(A) can each be independently hydrogen, alkyl, alkenyl, alkynyl,carbocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, orheterocyclyl(alkyl), each as defined herein. An N-carbamyl can besubstituted or unsubstituted.

An “O-thiocarbamyl” group refers to an “—OC(═S)N(R_(A)R_(B))” group inwhich R_(A) and R_(B) can each be independently hydrogen, alkyl,alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl,or heterocyclyl(alkyl), each as defined herein. An O-thiocarbamyl can besubstituted or unsubstituted.

An “N-thiocarbamyl” group refers to an “—N(R_(A))C(═S)OR” group in whichR and R_(A) can each be independently hydrogen, alkyl, alkenyl, alkynyl,carbocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, orheterocyclyl(alkyl), each as defined herein. An N-thiocarbamyl can besubstituted or unsubstituted.

A “C-amido” group refers to a “—C(═O)N(R_(A)R_(B))” group in which R_(A)and R_(B) can each be independently hydrogen, alkyl, alkenyl, alkynyl,carbocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, orheterocyclyl(alkyl), each as defined herein. A C-amido can besubstituted or unsubstituted.

An “N-amido” group refers to an “—N(R_(A))C(═O)R” group in which R andR_(A) can each be independently hydrogen, alkyl, alkenyl, alkynyl,carbocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, orheterocyclyl(alkyl), each as defined herein. An N-amido can besubstituted or unsubstituted.

Where the number of substituents is not specified (e.g., haloalkyl),there can be one or more substituents present. For example, “haloalkyl”can include one or more of the same or different halogens.

The term “solvate” refers to a complex or aggregate formed by one ormore molecules of a solute, e.g., a compound provided herein, and one ormore molecules of a solvent, which are present in stoichiometric ornon-stoichiometric amount. Suitable solvents include, but are notlimited to, water, methanol, ethanol, n-propanol, isopropanol, andacetic acid. In certain embodiments, the solvent is pharmaceuticallyacceptable. In one embodiment, the complex or aggregate is in acrystalline form. In another embodiment, the complex or aggregate is ina noncrystalline form. Where the solvent is water, the solvate is ahydrate. Examples of hydrates include, but are not limited to, ahemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, andpentahydrate.

It is understood that, in any compound described herein having one ormore chiral centers, if an absolute stereochemistry is not expresslyindicated, then each center may independently be of R-configuration orS-configuration or a mixture thereof. Thus, the compounds providedherein can be enantiomerically pure or enantiomerically enriched, or canbe stereoisomeric mixtures, and include all diastereomeric andenantiomeric forms. In addition, it is understood that, in any compounddescribed herein having one or more double bond(s) generatinggeometrical isomers that can be defined as E or Z, each double bond canindependently be E or Z or a mixture thereof. Stereoisomers areobtained, if desired, by methods such as, stereoselective synthesisand/or the separation of stereoisomers by chiral chromatographiccolumns. Likewise, it is understood that, in any compound described, alltautomeric forms are also intended to be included.

Wherever a substituent is depicted as a di-radical (i.e., has two pointsof attachment to the rest of a molecule), it is to be understood thatthe substituent can be attached in any directional configuration unlessotherwise indicated. For example, unless a particular orientation isspecified, the formula -AE- represents both -AE- and -EA-. In addition,if a group or substituent is depicted as

and when L is defined as a bond or absent; such group or substituent isequivalent to

In addition, when a group is depicted as a di-radical, such as X or ringA in Formula (II), one of ordinary skill in the art understands that thedefinition of such a group should also be di-radical. For example, whenX is defined as phenyl, 5 to 6 membered heteroaryl, 5 to 6 memberedheterocyclyl, or C₃-C₈ cycloalkyl, one skilled in the art understandsthat X is a phenylene, 5 to 6 membered heteroarylene, 5 to 6 memberedheterocyclylene, or C₃-C₈ cycloalkylene.

It is to be understood that, where a compound disclosed herein has anunfilled valency, the valency is to be filled with hydrogen ordeuterium.

It is understood that the compounds described herein can be labeledisotopically or by another other means, including, but not limited to,the use of chromophores or fluorescent moieties, bioluminescent labels,or chemiluminescent labels. Substitution with isotopes such as deuteriumcan afford certain therapeutic advantages from greater metabolicstability, such as, for example, increased in vivo half-life or reduceddosage requirements. Each chemical element as represented in a compoundstructure may include any isotope of said element. For example, in acompound structure, a hydrogen atom may be explicitly disclosed orunderstood to be present in the compound. At any position of thecompound that a hydrogen atom may be present, the hydrogen atom can beany isotope of hydrogen, including, but not limited to, hydrogen-1(protium), hydrogen-2 (deuterium), and hydrogen-3 (tritium). Thus, areference herein to a compound encompasses all potential isotopic formsunless the context clearly dictates otherwise.

It is understood that the methods and formulations described hereininclude the use of crystalline forms, amorphous phases, and/orpharmaceutically acceptable salts, solvates, hydrates, and conformers ofthe compounds provided herein, as well as metabolites and activemetabolites of these compounds having the same type of activity. Aconformer is a structure that is a conformational isomer. Conformationalisomerism is the phenomenon of a molecule with the same structuralformula but different conformations (conformers) of atoms about arotating bond. In certain embodiments, the compounds described hereinexist in solvated forms with pharmaceutically acceptable solvents suchas water or ethanol. In certain embodiments, the compounds providedherein exist in unsolvated form. Solvates contain either stoichiometricor non-stoichiometric amounts of a solvent and may be formed during theprocess of crystallization with pharmaceutically acceptable solventssuch as water or ethanol. Hydrates are formed when the solvent is water,or alcoholates are formed when the solvent is alcohol. In addition, thecompounds provided herein can exist in unsolvated as well as solvatedforms. Other forms in which the compounds provided herein can beprovided include amorphous forms, milled forms, and nano-particulateforms.

Likewise, it is understood that a compound described herein include thecompound in any of the forms described herein (e.g., pharmaceuticallyacceptable salts, crystalline forms, amorphous form, solvated forms,enantiomeric forms, and tautomeric forms).

As used herein, the abbreviations for any protective groups, aminoacids, and other compounds are, unless indicated otherwise, in accordwith their common usage, recognized abbreviations, or the IUPAC-IUBCommission on Biochemical Nomenclature (See, Eur. J. Biochem. 1992, 204,1-3).

The term “protecting group” as used herein refer to any atom or group ofatoms that is added to a molecule in order to prevent existing groups inthe molecule from undergoing unwanted chemical reactions. Examples ofprotecting group moieties are described in Greene and Wuts, ProtectiveGroups in Organic Synthesis, 3rd. Ed. John Wiley & Sons, 1999; and inMcOmie, Protective Groups in Organic Chemistry, Plenum Press, 1973; eachof which is hereby incorporated by reference for the limited purpose ofdisclosing suitable protecting groups. The protecting group moiety maybe chosen in such a way that they are stable to certain reactionconditions and readily removed at a convenient stage using methodologyknown in the art.

Generally, the nomenclature used herein and the laboratory procedures inorganic chemistry, medicinal chemistry, biochemistry, biology, andpharmacology described herein are those well-known and commonly employedin the art. Unless defined otherwise, all technical and scientific termsused herein generally have the same meaning as commonly understood byone of ordinary skill in the art to which this disclosure belongs.

The term “subject” refers to an animal, including, but not limited to, aprimate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit,rat, or mouse. The terms “subject” and “patient” are usedinterchangeably herein in reference, for example, to a mammaliansubject, such as a human subject. In one embodiment, the subject is ahuman.

The terms “treat,” “treating,” and “treatment” are meant to includealleviating or abrogating a disorder, disease, or condition, or one ormore of the symptoms associated with the disorder, disease, orcondition; or alleviating or eradicating the cause(s) of the disorder,disease, or condition itself.

The terms “prevent,” “preventing,” and “prevention” are meant to includea method of delaying and/or precluding the onset of a disorder, disease,or condition, and/or its attendant symptoms; barring a subject fromacquiring a disorder, disease, or condition; or reducing a subject'srisk of acquiring a disorder, disease, or condition.

The terms “alleviate” and “alleviating” refer to easing or reducing oneor more symptoms (e.g., pain) of a disorder, disease, or condition. Theterms can also refer to reducing adverse effects associated with anactive ingredient. Sometimes, the beneficial effects that a subjectderives from a prophylactic or therapeutic agent do not result in a cureof the disorder, disease, or condition.

The term “contacting” or “contact” is meant to refer to bringingtogether of a therapeutic agent and a biological molecule (e.g., aprotein, enzyme, RNA, or DNA), cell, or tissue such that a physiologicaland/or chemical effect takes place as a result of such contact.Contacting can take place in vitro, ex vivo, or in vivo. In oneembodiment, a therapeutic agent is contacted with a biological moleculein vitro to determine the effect of the therapeutic agent on thebiological molecule. In another embodiment, a therapeutic agent iscontacted with a cell in cell culture (in vitro) to determine the effectof the therapeutic agent on the cell. In yet another embodiment, thecontacting of a therapeutic agent with a biological molecule, cell, ortissue includes the administration of a therapeutic agent to a subjecthaving the biological molecule, cell, or tissue to be contacted.

The term “therapeutically effective amount” or “effective amount” ismeant to include the amount of a compound that, when administered, issufficient to prevent development of, or alleviate to some extent, oneor more of the symptoms of the disorder, disease, or condition beingtreated. The term “therapeutically effective amount” or “effectiveamount” also refers to the amount of a compound that is sufficient toelicit a biological or medical response of a biological molecule (e.g.,a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human,which is being sought by a researcher, veterinarian, medical doctor, orclinician.

The term “IC₅₀” or “EC₅₀” refers to an amount, concentration, or dosageof a compound that is required for 50% inhibition of a maximal responsein an assay that measures such a response.

The term “pharmaceutically acceptable carrier,” “pharmaceuticallyacceptable excipient,” “physiologically acceptable carrier,” or“physiologically acceptable excipient” refers to a pharmaceuticallyacceptable material, composition, or vehicle, such as a liquid or solidfiller, diluent, solvent, or encapsulating material. In one embodiment,each component is “pharmaceutically acceptable” in the sense of beingcompatible with the other ingredients of a pharmaceutical formulation,and suitable for use in contact with the tissue or organ of a subject(e.g., a human or an animal) without excessive toxicity, irritation,allergic response, immunogenicity, or other problems or complications,and commensurate with a reasonable benefit/risk ratio. See, e.g.,Remington: The Science and Practice of Pharmacy, 22nd ed.; Allen Ed.;Pharmaceutical Press: London, 2012; Handbook of PharmaceuticalExcipients, 8th ed.; Sheskey et al., Eds.; Pharmaceutical Press: London,2017; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.;Synapse Information Resources: 2007; Pharmaceutical Preformulation andFormulation, 2nd ed.; Gibson Ed.; Drugs and the Pharmaceutical Sciences199; Informa Healthcare: New York, N.Y., 2009.

The term “about” or “approximately” means an acceptable error for aparticular value as determined by one of ordinary skill in the art,which depends in part on how the value is measured or determined. Incertain embodiments, the term “about” or “approximately” means within 1,2, or 3 standard deviations. In certain embodiments, the term “about” or“approximately” means within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%,3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

Compounds of Formula (I)

In one embodiment, provided herein is a compound of Formula (I):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

-   -   R^(Het) is

-   -   each of X and X¹ is independently CH₂, C═O, SO, SO₂, or        CH₂C(═O);    -   each Y is independently H, deuterium, halogen, or optionally        substituted C₁-C₆ alkyl;    -   each R¹ is independently deuterium, hydroxyl, halogen, nitro,        cyano, —NR⁹R¹⁰, —NR⁹C(═O)R¹¹, —NR⁹SO₂R¹¹, —N(C(═O)R⁹)(C(═O)R¹¹),        optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆        alkoxy, optionally substituted C₃-C₇ cycloalkyl, optionally        substituted 3 to 10 membered heterocyclyl, optionally        substituted C₆-C₁₀ aryl, or optionally substituted 5 to 10        membered heteroaryl;    -   R² is hydroxyl, —NR⁹R¹⁰, optionally substituted C₁-C₆ alkyl,        optionally substituted C₃-C₇ cycloalkyl, optionally substituted        3 to 10 membered heterocyclyl, optionally substituted C₆-C₁₀        aryl, or optionally substituted 5 to 10 membered heteroaryl;    -   each of R³, R⁶, and R⁷ is independently H, deuterium, halogen,        optionally substituted C₁-C₆ alkyl, C₁-C₆ haloalkyl, optionally        substituted C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, optionally        substituted C₃-C₇ cycloalkyl, optionally substituted 3 to 10        membered heterocyclyl, optionally substituted C₆-C₁₀ aryl, or        optionally substituted 5 to 10 membered heteroaryl;    -   each of R⁴ and R⁵ is independently optionally substituted C₁-C₆        alkyl, optionally substituted C₃-C₇ cycloalkyl, optionally        substituted (C₃-C₇ cycloalkyl)C₁-C₆ alkyl, optionally        substituted 3 to 10 membered heterocyclyl, optionally        substituted (3 to 10 membered heterocyclyl)C₁-C₆ alkyl,        optionally substituted C₆-C₁₀ aryl, optionally substituted        C₇-C₁₄ aralkyl, optionally substituted 5 to 10 membered        heteroaryl, or (optionally substituted 5 to 10 membered        heteroaryl)C₁-C₆ alkyl;    -   R⁸ is H or deuterium;    -   each of R⁹ and R¹⁰ is independently H, optionally substituted        C₁-C₆ alkyl, C₁-C₆ haloalkyl, (C₁-C₆ alkoxy)C₁-C₆ alkyl,        optionally substituted C₃-C₇ cycloalkyl, optionally substituted        3 to 10 membered heterocyclyl, optionally substituted C₆-C₁₀        aryl, optionally substituted C₇-C₁₄ aralkyl, or optionally        substituted 5 to 10 membered heteroaryl; and    -   R¹¹ is optionally substituted C₁-C₆ alkyl, C₁-C₆ haloalkyl,        (C₁-C₆ alkoxy)C₁-C₆ alkyl, optionally substituted C₃-C₇        cycloalkyl, optionally substituted (C₃-C₇ cycloalkyl)C₁-C₆        alkyl, optionally substituted 3 to 10 membered heterocyclyl,        optionally substituted (3 to 10 membered heterocyclyl)C₁-C₆        alkyl, optionally substituted C₆-C₁₀ aryl, optionally        substituted C₇-C₁₄ aralkyl, optionally substituted 5 to 10        membered heteroaryl, or (optionally substituted 5 to 10 membered        heteroaryl)C₁-C₆ alkyl;    -   provided that at least one of R², R⁴, and R⁵ is optionally        substituted C₃-C₇ cycloalkyl.

In certain embodiments, in Formula (I), R^(H)et is

In certain embodiments, both X and X¹ are C═O. In certain embodiments, Xis C═O and X¹ is CH₂. In certain embodiments, Y is H.

In certain embodiments, in Formula (I), R¹ is —NR⁹R¹⁰, —NR⁹C(═O)R¹¹,—NR⁹SO₂R¹¹ or —N(C(═O)R⁹)(C(═O)R¹¹), wherein each R⁹, R¹⁰, and R¹¹ is asdefined herein. In certain embodiments, R¹ is —NR⁹C(═O)R¹¹, wherein R⁹is H or C₁-C₆ alkyl; and R¹¹ is as defined herein. In certainembodiments, R¹ is —NHC(═O)R¹¹, wherein R¹¹ is as defined herein. Incertain embodiments, R¹¹ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, (C₁-C₆alkoxy)C₁-C₆ alkyl, C₃-C₇ cycloalkyl, or (C₃-C₇ cycloalkyl)C₁-C₆ alkyl.In certain embodiments, R¹¹ is methyl, ethyl, isopropyl, t-butyl,—CH(C₂H₅)₂, trifluoromethyl, —CH(CF₃)CH₃, —CH₂OCH₃, cyclopropyl, or—CH₂-cyclopropyl.

In certain embodiments, in Formula (I), each of R³, R⁶, and R⁷ isindependently H, halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In certainembodiments, each of R³, R⁶, and R⁷ is H. In certain embodiments, atleast one of R³, R⁶, and R⁷ is halogen (e.g., fluoro or chloro) or C₁-C₆alkyl (e.g., methyl, ethyl, isopropyl, or t-butyl).

In certain embodiments, in Formula (I), R² is optionally substitutedC₃-C₇ cycloalkyl. In certain embodiments, R² is C₃-C₇ cycloalkyloptionally substituted with one or more substituents, each of which isindependently halogen, C₁-C₆ haloalkyl, or C₁-C₆ alkyl. In certainembodiments, R² is cyclopropyl optionally substituted with fluoro. Incertain such embodiments, each of R⁴ and R⁵ is independently C₁-C₆alkyl, for example, in one embodiment, R⁴ is ethyl and R⁵ is methyl.

In certain embodiments, Formula (I), R² is C₁-C₆ alkyl, for example, inone embodiment, methyl, ethyl, isopropyl, or t-butyl. In certain suchembodiments, one of R⁴ and R⁵ is optionally substituted C₃-C₇ cycloalkyland the other one of R⁴ and R⁵ is C₁-C₆ alkyl or C₁-C₆ haloalkyl. Incertain embodiments, one of R⁴ and R⁵ is cyclopropyl and the other oneof R⁴ and R⁵ is methyl. In certain embodiments, R⁴ is C₃-C₇ cycloalkyland R⁵ is C₁-C₆ alkyl. In certain embodiments, R⁴ is cyclopropyl and R⁵is methyl.

In one embodiment, provided here is a compound of Formula (I-A):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, X, X¹, and Y are each as defined herein.

In another embodiment, provided here is a compound of Formula (I-B):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, X, X¹, and Y are each as defined herein.

In yet another embodiment, provided here is a compound of Formula (I-C):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, X, X¹, and Y are each as defined herein.

In certain embodiments, in Formula (I), (I-A), (I-B), or (I-C), R¹ is—NR⁹R¹⁰ or —NR⁹C(═O)R¹¹, wherein R⁹, R¹⁰, and R¹¹ are each as definedherein. In certain embodiments, in Formula (I), (I-A), (I-B), or (I-C),R¹ is —NH₂ or —NHC(═O)R¹¹, wherein R¹¹ is optionally substituted C₁-C₆alkyl or optionally substituted C₃-C₇ cycloalkyl. In certainembodiments, in Formula (I), (I-A), (I-B), or (I-C), R¹ is —NH₂ or—NHC(═O)R¹¹, wherein R¹¹ is methyl, trifluoromethyl, methoxymethyl, orcyclopropyl. In certain embodiments, in Formula (I), (I-A), (I-B), or(I-C), R¹ is amino, acetamido, trifluoroacetamido, methoxyacetamido, orcyclopropamido.

In certain embodiments, in Formula (I), (I-A), (I-B), or (I-C), R² isoptionally substituted C₁-C₆ alkyl or optionally substituted C₃-C₇cycloalkyl. In certain embodiments, in Formula (I), (I-A), (I-B), or(I-C), R² is methyl or cyclopropyl.

In certain embodiments, in Formula (I), (I-A), (I-B), or (I-C), R³ is Hor deuterium. In certain embodiments, in Formula (I), (I-A), (I-B), or(I-C), R⁶ is H or deuterium. In certain embodiments, in Formula (I),(I-A), (I-B), or (I-C), R⁷ is H or deuterium. In certain embodiments, inFormula (I), (I-A), (I-B), or (I-C), R⁸ is H or deuterium.

In certain embodiments, in Formula (I), (I-A), (I-B), or (I-C), R⁴ isoptionally substituted C₁-C₆ alkyl or optionally substituted C₃-C₇cycloalkyl. In certain embodiments, in Formula (I), (I-A), (I-B), or(I-C), R⁴ is methyl, ethyl, or cyclopropyl.

In certain embodiments, in Formula (I), (I-A), (I-B), or (I-C), R⁵ isoptionally substituted C₁-C₆ alkyl or optionally substituted C₃-C₇cycloalkyl. In certain embodiments, in Formula (I), (I-A), (I-B), or(I-C), R⁵ is methyl, ethyl, or cyclopropyl.

In certain embodiments, in Formula (I), (I-A), (I-B), or (I-C), X isC(═O). In certain embodiments, in Formula (I), (I-A), (I-B), or (I-C),X¹ is CH₂ or C(═O). In certain embodiments, Y is H or deuterium.

In certain embodiments, in Formula (I), (I-A), (I-B), or (I-C), R¹ isamino or —NHC(═O)R¹¹, wherein R¹¹ is optionally substituted C₁-C₆ alkylor optionally substituted C₃-C₇ cycloalkyl; R² is optionally substitutedC₁-C₆ alkyl or optionally substituted C₃-C₇ cycloalkyl; R³, R⁶, R⁷, andR⁸ are each independently H or deuterium; R⁴ and R⁵ is eachindependently optionally substituted C₁-C₆ alkyl or optionallysubstituted C₃-C₇ cycloalkyl; X is C(═O); X¹ is CH₂ or C(═O); and Y is Hor deuterium.

In certain embodiments, in Formula (I), (I-A), (I-B), or (I-C), R¹ isamino, acetamido, trifluoroacetamido, methoxyacetamido, orcyclopropamido; R² is methyl or cyclopropyl; R³, R⁶, R⁷, and R⁸ are eachindependently H or deuterium; R⁴ and R⁵ is each independently methyl,ethyl, or cyclopropyl; X is C(═O); X¹ is CH₂ or C(═O); and Y is H ordeuterium.

In one embodiment, provided herein is:

or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is:

-   (S)-1-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione,-   (S)-1-amino-5-(1-(3-cyclopropoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione,-   (R)-1-amino-5-(1-(3-cyclopropoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione,-   (S)-1-amino-5-(1-(3-cyclopropoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione,-   (R)-1-amino-5-(1-(3-cyclopropoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione,    or-   (S)-3-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[2,3-c]pyrrol-6(5H)-one;    or a pharmaceutically acceptable salt thereof.

In yet another embodiment, provided herein is:

-   (S)-N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-2,2,2-trifluoroacetamide    A1,-   (S)-N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)-2-methoxyacetamide    A2,-   (S)-N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)cyclopropanecarboxamide    A3,-   (S)-N-(5-(1-(3-cyclopropoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)acetamide    A4,-   (R)-N-(5-(1-(3-cyclopropoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)acetamide    A5,-   (S)-N-(5-(2-(cyclopropylsulfonyl)-1-(3-ethoxy-4-methoxyphenyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)acetamide    A6,-   (S)-N-(5-(2-(cyclopropylsulfonyl)-1-(3-ethoxy-4-methoxyphenyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-2,2,2-trifluoroacetamide    A7,-   (R)-N-(5-(2-(cyclopropylsulfonyl)-1-(3-ethoxy-4-methoxyphenyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-2,2,2-trifluoroacetamide    A8,-   (R)-N-(5-(2-(cyclopropylsulfonyl)-1-(3-ethoxy-4-methoxyphenyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-2-methoxyacetamide    A9,-   (R)-N-(5-(2-(cyclopropylsulfonyl)-1-(3-ethoxy-4-methoxyphenyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)acetamide    A10, or-   (S)-N-(5-(2-(cyclopropylsulfonyl)-1-(3-ethoxy-4-methoxyphenyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-2-methoxyacetamide    A11;    or a pharmaceutically acceptable salt thereof.

Compounds of Formula (II)

In one embodiment, provided herein is a compound of Formula (II):

R^(W)-L²-X-L¹-R¹  (II)

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

-   -   R¹ is

-   -   R^(W) is

-   -   X is C₁-C₁₅ alkylene, heteroalkylene, C₂-C₁₀ alkenylene, C₂-C₁₀        alkynylene, phenylene, five to six membered heteroarylene, three        to six membered heterocyclylene, or C₃-C₈ cycloalkylene, wherein        each of phenylene, five to six membered heteroarylene, three to        six membered heterocyclylene, or C₃-C₈ cycloalkylene is        optionally substituted with one or more R¹⁸; or X is C₁-C₁₅        alkylene, heteroalkylene, C₂-C₁₀ alkenylene, or C₂-C₁₀        alkynylene, wherein one or more methylene repeating units is        replaced by a ring structure selected from the group consisting        of phenylene, five to six membered heteroarylene, three to six        membered heterocyclylene, or C₃-C₈ cycloalkylene, and wherein        each ring structure is optionally substituted with one or more        R¹⁸;    -   each Y is independently CH₂, O, S, or NH;    -   L¹ is a bond,

-   -   L² is a bond, —O—, —S—, —NR^(16a)—, —(CH₂)₁₋₃—, —C(═O)—, or        —(CH₂)₀₋₃C(═O)NR^(16a)—    -   each Q is independently CH₂ or C(═O);    -   each of Q¹, Q², and Q³ is independently S or CH, provided that        one of Q¹, Q², and Q³ is S;    -   each R^(A) is independently deuterium, hydroxyl, halogen, cyano,        nitro, optionally substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,        optionally substituted amino, C₁-C₆ alkylamino, (amino)C₁-C₆        alkyl, —(C═O)NR^(17a)R^(17b), (C₁-C₆ alkoxy)C₁-C₆ alkyl,        —O—(C₁-C₆ alkoxy)C₁-C₆ alkyl, or optionally substituted C₃-C₇        cycloalkyl;    -   each of R², R^(2a) and R^(2b) is independently H, deuterium,        halogen, or C₁-C₆ alkyl;    -   each R^(2c) is independently H, C₁-C₆ alkyl, or C₃-C₈        cycloalkyl, wherein the C₃-C₈ cycloalkyl is optionally        substituted with C₁-C₆ alkyl, halogen, or C₁-C₆ haloalkyl;    -   each R^(2d) is independently H, OH, halogen, —O—C₁-C₆ alkyl,        —O—C₁-C₆ haloalkyl, or —O—C₃-C₈ cycloalkyl, wherein —O—C₃-C₈        cycloalkyl is optionally substituted with C₁-C₆ alkyl, halogen,        or C₁-C₆ haloalkyl;    -   each R^(2e) is independently —C(═O)—C₁-C₆ alkyl or —C(═O)—C₃-C₈        cycloalkyl, each optionally substituted with one or more        substituents, each of which is independently selected from the        group consisting of cyano, halogen, hydroxyl, amino, and C₁-C₆        haloalkyl;    -   each R³ is independently H, deuterium, C₁-C₆ alkyl,

-   -   each R⁴ is independently —NR^(4A)R^(4B), —NR^(4A)C(═O)R^(4C),        —NR^(4A)SO₂R^(4C), or —N(C(═O)R^(4A))(C(═O)R^(4C)).    -   each of R^(4A) and R^(4B) is independently H, optionally        substituted C₁-C₆ alkyl, C₁-C₆ haloalkyl, (C₁-C₆ alkoxy)C₁-C₆        alkyl, optionally substituted C₃-C₇ cycloalkyl, optionally        substituted 3 to 10 membered heterocyclyl, optionally        substituted C₆-C₁₀ aryl, optionally substituted C₇-C₁₄ aralkyl,        or optionally substituted 5 to 10 membered heteroaryl;    -   each R^(4C) is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl,        (C₁-C₆ alkoxy)C₁-C₆ alkyl, optionally substituted C₃-C₇        cycloalkyl, optionally substituted (C₃-C₇ cycloalkyl)C₁-C₆        alkyl, optionally substituted 3 to 10 membered heterocyclyl,        optionally substituted (3 to 10 membered heterocyclyl)C₁-C₆        alkyl, optionally substituted C₆-C₁₀ aryl, optionally        substituted C₇-C₁₄ aralkyl, optionally substituted 5 to 10        membered heteroaryl, or (optionally substituted 5 to 10 membered        heteroaryl)C₁-C₆ alkyl;    -   each R⁵ is independently H, deuterium, halogen, or optionally        substituted C₁-C₆ alkyl;    -   each R⁶ is independently hydroxyl, —NR^(4A)R^(4B), C₁-C₆ alkyl,        optionally substituted C₃-C₇ cycloalkyl, optionally substituted        3 to 10 membered heterocyclyl, optionally substituted C₆-C₁₀        aryl, or optionally substituted 5 to 10 membered heteroaryl;    -   each of R⁷, R¹⁰, and R¹¹ is independently H, deuterium, halogen,        C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,        optionally substituted C₃-C₇ cycloalkyl, optionally substituted        3 to 10 membered heterocyclyl, optionally substituted C₆-C₁₀        aryl, or optionally substituted 5 to 10 membered heteroaryl;    -   each of R⁸ and R⁹ is independently optionally substituted C₁-C₆        alkyl, C₁-C₆ haloalkyl, optionally substituted C₃-C₇ cycloalkyl,        optionally substituted (C₃-C₇ cycloalkyl)C₁-C₆ alkyl, optionally        substituted 3 to 10 membered heterocyclyl, optionally        substituted (3 to 10 membered heterocyclyl)C₁-C₆ alkyl,        optionally substituted C₆-C₁₀ aryl, optionally substituted        C₇-C₁₄ aralkyl, optionally substituted 5 to 10 membered        heteroaryl, or (optionally substituted 5 to 10 membered        heteroaryl)C₁-C₆ alkyl;    -   each R¹² is independently H or deuterium;    -   each of R¹³ and R¹⁴ is independently halogen, hydroxyl, cyano,        nitro, optionally substituted C₁-C₆ alkyl, C₁-C₆ haloalkyl,        C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, optionally substituted amino,        (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O—(C₁-C₆ alkoxy)C₁-C₆ alkyl, or        optionally substituted C₃-C₇ cycloalkyl;    -   each of R¹⁵, R¹⁶, R^(16a) and R^(16b) is independently H or        C₁-C₆ alkyl;    -   each R^(17a) and R^(17b) is independently H or C₁-C₆ alkyl, or        R^(17a) and R^(17b) together with the nitrogen atom to which        they are attached form 5 or 6 membered heterocyclyl, each        optionally substituted with one or more R¹⁸;    -   each R¹⁸ is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆        haloalkyl, C₁-C₆ haloalkoxy, (C₁-C₆ alkoxy)C₁-C₆ alkyl,        —O—(C₁-C₆ alkoxy)C₁-C₆ alkyl, optionally substituted amino,        halogen, or cyano; or two geminal R¹⁸ form oxo;    -   each of R^(19a) and R^(19b) is independently H, optionally        substituted C₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl,        optionally substituted C₂-C₆ alkynyl, optionally substituted        C₆-C₁₀ aryl, optionally substituted 5 to 10 membered heteroaryl,        optionally substituted C₇-C₁₄ aralkyl, optionally substituted 3        to 10 membered heterocyclyl, or optionally substituted C₃-C₈        carbocyclyl;    -   each of R^(20a) and R^(20b) is independently H, halogen, C₁-C₆        alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or C₃-C₈        carbocyclyl;    -   each of R^(21a) and R^(21b) is independently H, optionally        substituted C₁-C₆ alkyl, optionally substituted C₆-C₁₀ aryl,        optionally substituted C₇-C₁₄ aralkyl, or optionally substituted        C₃-C₈ carbocyclyl;    -   each of X¹ and X² is independently O or S;    -   each Z¹ is independently a bond, —(CR^(a)R^(b))_(q1)—, —C(═O)—,        —CH═CH—, or —C≡C—;    -   each Z² is independently —(CR^(c)R^(d))_(q2)—;    -   each of Z³ and Z⁴ is independently NR¹⁶, O, S, or a bond;    -   each of R^(a), R^(b), R^(c), and R^(d) is independently H,        halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,        C₁-C₆ haloalkoxy, or optionally substituted C₃-C₆ cycloalkyl;    -   each Ring A is independently phenylene, five to six membered        heteroarylene, three to six membered heterocyclylene, or C₃-C₈        cycloalkylene, each optionally substituted with one or more R¹⁸.    -   each of m1, m2, m3, m4, m5, m6, m7, m8, m9, k1, k2, k3, k4, k5,        k6, k7, k8, and k9 is independently an integer of 0, 1, 2, 3, 4,        or 5;    -   each n is independently an integer of 0, 1, or 2; and    -   each q1 and q2 is independently an integer of 1, 2, or 3.

In certain embodiments, in Formula (II), n is an integer of 1. Incertain embodiments, in Formula (II), n is an integer of 0 or 2.

In certain embodiments, in Formula (II), R¹ is

wherein R², R³, R^(A), and Q are each as defined herein. In certainembodiments, in Formula (II), R¹ is

wherein R², R³, and Q are each as defined herein. In certainembodiments, in Formula (II), R¹ is

wherein R², R³, and Q are each as defined herein. In certainembodiments, in Formula (II), R¹ is

wherein R², R³, and Q are each as defined herein. In certainembodiments, in Formula (II), R¹ is

wherein R², R³, and Q are each as defined herein. In certainembodiments, in Formula (II), R¹ is

wherein R², R³, and Q are each as defined herein. In certainembodiments, in Formula (II), R¹

wherein R², R³, and Q are each as defined herein. In certainembodiments, in Formula (II), R¹ is

wherein R², R³, R^(A), and Q are each as defined herein. In certainembodiments, in Formula (II), R¹ is

wherein R², R³, R^(A), and Q are each as defined herein.

In certain embodiments, in Formula (II), R¹ is unsubstituted. In certainembodiments, in Formula (II), R¹ is substituted with one R^(A). Incertain such embodiments, R^(A) is halogen (e.g., F) or optionallysubstituted C₁-C₆ alkyl. In certain embodiments, in Formula (II), R¹ is

wherein R^(B) is H or R^(A); and R², R³, R^(A), and Q are each asdefined herein.

In certain embodiments, in Formula (II), R¹ is

wherein R², R³, R^(B), are as defined herein. In certain embodiments,R^(B) is H, halogen, or optionally substituted C₁-C₆ alkyl. In certainembodiments, R^(B) is fluoro.

In certain embodiments, in Formula (II), R² is H. In certainembodiments, in Formula (II), R³ is H.

In certain embodiments, in Formula (II), R¹ is

In certain embodiments, in Formula (II), R¹ is

In certain embodiments, in Formula (II), R¹ is

In certain embodiments, in Formula (II), R¹ is

In certain embodiments, in Formula (II), R¹ is

In certain embodiments, in Formula (II), L¹ is a bond,

wherein R¹ is attached to Z¹; and ring A, R¹⁶, X¹, X², Z¹, Z², Z³, Z⁴,k1, k2, k3, k4, k5, k6, k7, k8, k9, m1, m2, m3, m4, m5, m6, m7, m8, andm9 are each as defined herein.

In certain embodiments, in Formula (II), L¹ is

wherein R¹⁶, X¹, Z¹, and m1 are each as defined herein; in oneembodiment, each R¹⁶ is H; X¹ is O; Z¹ is a bond or —(CH₂)₁₋₃—; and m1is an integer of 0 or 1. In one embodiment, in Formula (II), L¹ is

In certain embodiments, in Formula (II), L¹

wherein R¹⁶, X¹, Z¹, Z², Z³, and m3 are each as defined herein; in oneembodiment, Z³ is O or NR¹⁶; in another embodiment, each R¹⁶ is H; X¹ isO; Z² is —(CH₂)₁₋₂—; Z¹ is a bond or —(CH₂)₁₋₃—; and m3 is an integer of0 or 1. In certain embodiments, in Formula (II), L¹

In certain embodiments, in Formula (II), L¹ is

wherein Z¹, Z³, and m6 are each as defined herein; in one embodiment, Z³is O or NR¹⁶; in another embodiment, R¹⁶ is H; Z¹ is a bond or—(CH₂)₁₋₃—; and m6 is an integer of 0 or 1; in yet another embodiment,Z¹ is —C(O)—; Z³ is a bond; and m6 is an integer of 0 or 1. In certainembodiments, in Formula (I), L¹ is

wherein ring A, Z¹, Z³, Z⁴, k6, and m6 are each as defined herein; inone embodiment, Z³ is O or NR¹⁶; in another embodiment, ring A isphenylene optionally substituted with R¹⁸; Z¹ is a bond or —(CH₂)₁₋₃—;Z⁴ is —O— or —NR¹⁶—; each R¹⁶ is H; and k6 and m6 are each independentlyan integer of 0 or 1. In certain embodiments, in Formula (II), L¹ is

In certain embodiments, in Formula (II), L¹ is

wherein each Z¹ and m7 is as defined herein; in one embodiment, each Z¹is independently a bond or —(CH₂)₁₋₃—; and each m7 is independently aninteger of 0 or 1. In one embodiment, L¹ is

In certain embodiments, in Formula (II), L¹ is

wherein each Z³ is independently NR¹⁶; and R¹⁶, X¹, Z¹, Z², Z³, and m8are each as defined herein; in one embodiment, Z¹ is —C≡C—; in anotherembodiment, X¹ is O; Z² is —CH₂—; R¹⁶ is H; and each m8 is independentlyan integer of 0 or 1. In certain embodiments, in Formula (II), L¹ is

wherein each X¹, Z¹, Z², Z³, and m9 is as defined herein; in oneembodiment, Z¹ is a bond; X¹ is O; and each m9 is independently aninteger of 0 or 1. In one embodiment, in Formula (II), L¹ is

In certain embodiments, in Formula (II), L¹ is

wherein each Z⁴ is independently O or NR¹⁶; and ring A, R¹⁶, Z¹, k7, andm7 are each as defined herein; in one embodiment, each ring A isindependently phenylene, 6 membered heterocyclylene, or C₆-C₈cycloalkylene; each R¹⁶ is independently H or methyl; Z¹ is a bond; eachk7 is independently an integer of 0 or 1; and each m7 is independentlyan integer of 0, 1, or 2. In certain embodiments, in Formula (II), L¹ is

In any embodiments of L¹ that contains ring A, ring A can be aphenylene; five or six membered heteroarylene containing one, two, orthree heteroatoms, each independently selected from the group consistingof N, O, and S; five or six membered heterocyclylene containing one ortwo heteroatoms, each independently selected from the group consistingof N, O, and S; or C₃-C₈ cycloalkylene (in one embodiment, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,bicyclo[2.2.1]heptanyl, or bicyclo[2.2.2]octanyl). In certainembodiments, ring A is optionally substituted with one or more R¹⁸.

In one embodiment, in Formula (II), L¹ is —NH(CH₂)₂NHC(═O)—,—O(CH₂)₂NHC(═O)—, —NH—, —CH₂NHC(O)NH—,

In another embodiment, in Formula (II), L¹ is *—NH(CH₂)₂NHC(═O)—,*—O(CH₂)₂NHC(O)—,

*—CH₂NHC(O)NH—,

where * indicates the point of connection to R¹.

In certain embodiments, in Formula (II), R¹-L¹ is

In certain embodiments, provided herein is a compound of Formula (Ia),(Ib), (IIc), or (IId):

wherein R^(W), L², and X are each as defined herein.

In certain embodiments, in Formula (II), (IIa), (IIb), (IIc), or (IId),L² is a bond. In certain embodiments, in Formula (II), (IIa), (IIb),(IIc), or (IId), L² is —O—. In certain embodiments, in Formula (II),(IIa), (IIb), (IIc), or (IId), L² is —NR^(16a)—, wherein R^(16a) is asdefined herein. In certain embodiments, in Formula (II), (IIa), (IIb),(IIc), or (IId), L² is —(CH₂)₁₋₂—. In certain embodiments, in Formula(II), (IIa), (IIb), (IIc), or (IId), L² is —C(═O)—. In certainembodiments, in Formula (II), (IIa), (IIb), (IIc), or (IId), L² is—CH₂C(═O)NR^(16a)—, wherein R^(16a) is as defined herein. In certainembodiments, R^(16a) is H. In certain embodiments, R^(16a) is methyl. Incertain embodiments, in Formula (II), (IIa), (IIb), (IIc), or (IId), L²is —CH₂C(═O)NH—*, where * indicates the point of connection to X. Incertain embodiments, in Formula (II), (IIa), (IIb), (IIc), or (IId), L¹and L² cannot both be a bond.

In certain embodiments, in Formula (II), (IIa), (IIb), (IIc), or (IId),X is alkylene. In certain embodiments, in Formula (II), (IIa), (IIb),(IIc), or (IId), X is C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂,C₁₃, C₁₄, or C₁₅ alkylene. In certain embodiments, in Formula (II),(IIa), (IIb), (IIc), or (IId), X is C₁-C₈ alkylene. In certainembodiments, in Formula (II), (IIa), (IIb), (IIc), or (IId), X ismethylene, ethylene, propylene, butylene, pentylene, hexylene,heptylene, or octylene. In certain embodiments, in Formula (II), (IIa),(IIb), (IIc), or (IId), X is straight-chained alkylene. In certainembodiments, in Formula (II), (IIa), (IIb), (IIc), or (IId), X isstraight-chained C₁-C₈ alkylene. In certain embodiments, in Formula(II), (IIa), (IIb), (IIc), or (IId), X is unsubstituted. In certainembodiments, in Formula (II), (IIa), (IIb), (IIc), or (IId), X isunsubstituted C₇ alkylene. In certain embodiments, in Formula (II),(IIa), (IIb), (IIc), or (IId), X is —(CH₂)₅—, —(CH₂)₆—, —(CH₂)₇—, or—(CH₂)₈—.

In certain embodiments, in Formula (II), (IIa), (IIb), (IIc), or (IId),X is heteroalkylene. In certain embodiments, in Formula (II), (IIa),(IIb), (IIc), or (IId), X is C₁-C₁₅ alkylene, wherein one or moremethylene units are replaced by a heteroatom. In certain embodiments,the heteroatom in the heteroalkylene is oxygen (O), nitrogen (N), orsulfur (S). In certain embodiments, in Formula (II), (IIa), (IIb),(IIc), or (IId), X is a heteroalkylene containing carbon, hydrogen, andoxygen atoms, wherein at least one methylene unit is replaced by oxygen.In certain embodiments, in Formula (II), (IIa), (IIb), (IIc), or (IId),X is —(CH₂CH₂O)₁₋₅— or —(CH₂CH₂O)₁₋₅CH₂CH₂—. In certain embodiments, inFormula (II), (IIa), (IIb), (IIc), or (IId), X is heteroalkylenecontaining carbon, hydrogen, and nitrogen atoms, wherein at least onemethylene unit is replaced by NR^(16c), wherein R¹⁶, is as definedherein. In certain embodiments, in Formula (II), (IIa), (IIb), (IIc), or(IId), X is —(CH₂)₁₋₅—NR^(16c)—(CH₂)₁₋₅—, wherein R¹⁶, is H or C₁-C₆alkyl, in one embodiment, methyl. In certain embodiments, in Formula(II), (IIa), (IIb), (IIc), or (IId), X is unsubstituted heteroalkylenecontaining carbon, hydrogen, and oxygen and/or nitrogen atoms. Incertain embodiments, in Formula (II), (IIa), (IIb), (IIc), or (IId), Xis straight-chained heteroalkylene. In certain embodiments, in Formula(II), (IIa), (IIb), (IIc), or (IId), X is —CH₂CH₂O—, —(CH₂CH₂O)₂—,—(CH₂CH₂O)₃—, —CH₂CH₂OCH₂CH₂—, —(CH₂CH₂O)₂CH₂CH₂—, —(CH₂CH₂O)₃CH₂CH₂—,—(CH₂CH₂O)₄CH₂CH₂—, —CH₂NR^(16c)CH₂—, —CH₂CH₂NR^(16c)CH₂CH₂—,—(CH₂)₂OCH₂(CH₂)₃—, or —(CH₂)₃NR^(16c)(CH₂)₃—, wherein each R^(16c) isas defined herein. In certain embodiments, R^(16c) is H or methyl. Incertain embodiments, in Formula (II), (IIa), (IIb), (IIc), or (IId), Xis phenylene; five or six membered heteroarylene containing one, two, orthree heteroatoms, each independently selected from the group consistingof N, O, and S; five or six membered heterocyclylene containing one ortwo heteroatoms, each independently selected from the group consistingof N, O, and S; or C₃-C₈ cycloalkylene (in one embodiment, cyclopropyl,cyclobutylene, cyclopentylene, cyclohexylene, or cycloheptylene); eachof which is optionally substituted with one or more R¹⁸, wherein eachR¹⁸ is as defined herein. In certain embodiments, in Formula (II),(IIa), (IIb), (IIc), or (IId), X is C₁-C₈ alkylene or heteroalkylene,wherein at least one methylene unit is replaced by a ring structureselected from 5 or 6 membered heteroarylene containing one, two or threeheteroatoms, each independently selected from the group consisting of N,O, and S; five or six membered heterocyclylene containing one or twoheteroatoms, each independently selected from the group consisting of N,O, and S; and C₃-C₈ cycloalkylene (in one embodiment, cyclopropylene,cyclobutylene, cyclopentylene, cyclohexylene, or cycloheptylene); eachof which is optionally substituted with one or more R¹⁸, wherein eachR¹⁸ is as defined herein.

In certain embodiments, Formula (II), (IIa), (IIb), (IIc), or (IId),R^(W) is

wherein R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R^(16b), and Q are each asdefined herein. In certain such embodiments, each of R⁵, R⁷, R¹⁰, R¹¹,and R¹² is H. In certain such embodiments, R⁶ is C₁-C₆ alkyl (e.g.,methyl) or C₃-C₇ cycloalkyl (e.g., cyclopropyl). In certain suchembodiments, each R⁸ and R⁹ is independently C₁-C₆ alkyl orC₁-C₆haloalkyl; for example, R⁸ is ethyl and R⁹ is methyl. In certainembodiments, R^(W) is

In certain embodiments, in Formula (II), (IIa), (IIb), (IIc), or (IId),R^(W) is

wherein each R⁴, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R^(16b), R^(A), and Q isas defined herein. In certain such embodiments, R^(A) is absent,halogen, or C₁-C₆ alkyl; and each of R⁷, R¹⁰, R¹¹, and R¹² is H. Incertain such embodiments, R⁴ is —NR^(4A)C(═O)R^(4C); R^(4A) is H; andR^(4C) is C₁-C₆ alkyl, C₁-C₆ haloalkyl, (C₁-C₆ alkoxy)C₁-C₆ alkyl orC₃-C₇ cycloalkyl. In certain such embodiments, R^(4C) is methyl, ethyl,isopropyl, t-butyl, —CH(C₂H₅)₂, trifluoromethyl, —CH(CF₃)CH₃, —CH₂OCH₃,or cyclopropyl. In certain such embodiment, R^(4C) is methyl. In certainsuch embodiments, each R⁶, R⁸ and R⁹ is independently C₁-C₆alkyl, C₁-C₆haloalkyl, or C₃-C₇ cycloalkyl. In certain embodiments, R^(W) is

In one embodiment, provided herein is a compound of Formula (III):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R³,R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R^(16b), R^(A), L¹, L²,Q, Q¹, Q², Q³, X,and n are each as defined herein.

In another embodiment, provided herein is a compound of Formula (IV):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R³,R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R^(16b), R^(A), L¹, L², Q, and X are eachas defined herein.

In yet another embodiment, provided herein is a compound of Formula (V):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R⁶, R⁸,R⁹, L¹, L², and X are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula(VI):

or a diastereomer, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;wherein R⁶, R⁸, R⁹, L¹, L², and X are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula(VII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R⁶, R⁸,R⁹, L², and X are each as defined herein.

In still another embodiment, provided herein is a compound of Formula(VIII):

or a diastereomer, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;wherein R⁶, R⁸, R⁹, L², and X are each as defined herein.

In one embodiment, provided herein is a compound of Formula (IX):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R³,R⁴, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R^(A), L¹, L², Q, Q¹, Q², Q³, X, andn are each as defined herein.

In another embodiment, provided herein is a compound of Formula (X):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R³,R⁴, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², L¹, L², Q, and X are each as definedherein.

In yet another embodiment, provided herein is a compound of Formula(XI):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R⁴, R⁶,R⁸, R⁹, L¹, L², and X are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula(XII):

or a diastereomer, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;wherein R⁴, R⁶, R⁸, R⁹, L¹, L², and X are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula(XIII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R⁴, R⁶,R⁸, R⁹, L², and X are each as defined herein.

In still another embodiment, provided herein is a compound of Formula(XIV):

or a diastereomer, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;wherein R⁴, R⁶, R⁸, R⁹, L², and X are each as defined herein.

In one embodiment, provided herein is a compound of Formula (XV):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R³,R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R^(16b), R^(A), L¹, L², Q, X, and n areeach as defined herein.

In one embodiment, provided herein is a compound of Formula (XVI):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R³,R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R^(16b), R^(A), R^(B), L¹, L², Q, and Xare each as defined herein.

In another embodiment, provided herein is a compound of Formula (XVII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R⁶, R⁸,R⁹, R^(B), L¹, L², and X are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula(XVIII):

or a diastereomer, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;wherein R⁶, R⁸, R⁹, R^(B), L¹, L², and X are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula(XIX):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R⁶, R⁸,R⁹, R^(B), L², and X are each as defined herein.

In still another embodiment, provided herein is a compound of Formula(XX):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R⁶, R⁸,R⁹, R^(B), L², and X are each as defined herein.

In one embodiment, provided herein is a compound of Formula (XXI):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R³,R⁴, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R^(A), R^(B), L¹, L², Q, and X areeach as defined herein.

In one embodiment, provided herein is a compound of Formula (XXII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R³,R⁴, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R^(B), L¹, L², Q, and X are each asdefined herein.

In another embodiment, provided herein is a compound of Formula (XXIII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R⁴, R⁶,R⁸, R⁹, R^(B), L¹, L², and X are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula(XXIV):

or a diastereomer, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;wherein R⁴, R⁶, R⁸, R⁹, R^(B), L¹, L², and X are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula(XXV):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R⁴, R⁶,R⁸, R⁹, R^(B), L², and X are each as defined herein.

In still another embodiment, provided herein is a compound of Formula(XXVI):

or a diastereomer, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;wherein R⁴, R⁶, R⁸, R⁹, R^(B), L², and X are each as defined herein.

In one embodiment, provided herein is a compound of Formula (XXVII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R³,R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R^(16b), R^(A), R^(B), L¹, L², Q, and Xare each as defined herein.

In another embodiment, provided herein is a compound of Formula(XXVIII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R⁶, R⁸,R⁹, R^(B), L¹, L², and X are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula(XXIX):

or a diastereomer, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;wherein R⁶, R⁸, R⁹, R^(B), L¹, L², and X are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula(XXX):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R⁶, R⁸,R⁹, R^(B), L², and X are each as defined herein.

In still another embodiment, provided herein is a compound of Formula(XXXI):

or a diastereomer, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;wherein R⁶, R⁸, R⁹, R^(B), L², and X are each as defined herein.

In one embodiment, provided herein is a compound of Formula (XXXII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R³,R⁴, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R^(B), L¹, L², Q, and X are each asdefined herein.

In one embodiment, provided herein is a compound of Formula (XXXIII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R³,R⁴, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R^(B), L¹, L², Q, and X are each asdefined herein.

In another embodiment, provided herein is a compound of Formula (XXXIV):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R⁴, R⁶,R⁸, R⁹, R^(B), L¹, L², and X are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula(XXXV):

or a diastereomer, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;wherein R⁴, R⁶, R⁸, R⁹, R^(B), L¹, L², and X are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula(XXXVI):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R⁴, R⁶,R⁸, R⁹, R^(B), L², and X are each as defined herein.

In still another embodiment, provided herein is a compound of Formula(XXXVII):

or a diastereomer, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;wherein R⁴, R⁶, R⁸, R⁹, R^(B), L², and X are each as defined herein.

In one embodiment, provided herein is a compound of Formula (XXXVIII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R⁶, R⁷,R⁸, R⁹, R¹⁰, R¹¹, R¹², R^(2c), R^(2d), R^(16b), R^(A), L¹, L², Q, and Xare each as defined herein.

In another embodiment, provided herein is a compound of Formula (XXXIX):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R⁶, R⁸,R⁹, L¹, L², and X are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula(XL):

or a diastereomer, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;wherein R⁶, R⁸, R⁹, L¹, L², and X are each as defined herein.

In one embodiment, provided herein is a compound of Formula (XLI):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R⁴, R⁶,R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R^(2c), R^(2d), R^(A), L¹, L², Q, and X areeach as defined herein.

In one embodiment, provided herein is a compound of Formula (XLII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R⁴, R⁶,R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R^(2c)R^(2d), L¹, L², Q, and X are each asdefined herein.

In another embodiment, provided herein is a compound of Formula (XLIII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R⁴, R⁶,R⁸, R⁹, L¹, L², and X are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula(XLIV):

or a diastereomer, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;wherein R⁴, R⁶, R⁸, R⁹, L¹, L², and X are each as defined herein.

In certain embodiments, in any one of Formulae (II) to (XLIV), L¹, ifpresent, is a bond, —NH—, pyrrolidin-1,3-diyl, piperidin-1,3-diyl,piperidin-1,4-diyl,

In certain embodiments, in any one of Formulae (II) to (XIL), L¹, ifpresent, is a bond, —NH—, piperidin-1,4-diyl,

In certain embodiments, in any one of Formulae (II) to (XLIV) and (IIa)to (IId), L² is a bond, —O—, —NH—, or —C(═O)NH—.

In certain embodiments, in any one of Formulae (II) to (XLIV) and (IIa)to (IId), X is propan-1,3-diyl, butan-1,4-diyl, pentan-1,5-diyl,hexan-1,6-diyl, heptan-1,7-diyl, octan-1,8-diyl, nonan-1,9-diyl,decan-1,10-diyl, undecan-1,11-diyl, dodecan-1,12-diyl,hept-1-yn-1,7-diyl,

In certain embodiments, in any one of Formulae (II) to (XLIV) and (IIa)to (IId), L¹, if present, is a bond, —NH—, pyrrolidin-1,3-diyl,piperidin-1,3-diyl, piperidin-1,4-diyl,

L² is a bond, —O—, —NH—, or —C(═O)NH—; and X is propan-1,3-diyl,butan-1,4-diyl, pentan-1,5-diyl, hexan-1,6-diyl, heptan-1,7-diyl,octan-1,8-diyl, nonan-1,9-diyl, decan-1,10-diyl, undecan-1,11-diyl,dodecan-1,12-diyl, hept-1-yn-1,7-diyl

In certain embodiments, in any one of Formulae (II) to (XLIV) and (IIa)to (IId), L¹, if present, is a bond, —NH—, piperidin-1,4-diyl,

L² is a bond, —O—, —NH—, or —C(═O)NH—; and X is propan-1,3-diyl,butan-1,4-diyl, pentan-1,5-diyl, hexan-1,6-diyl, heptan-1,7-diyl,octan-1,8-diyl, nonan-1,9-diyl, decan-1,10-diyl, undecan-1,11-diyl,dodecan-1,12-diyl, hept-1-1,7-diyl,

In certain embodiments, in Formula (II), (IIa), (IIb), (IIc), or (IId),R^(W) is

wherein each R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹³, R¹⁴, and R^(16b) is as definedherein. In certain such embodiments, each R¹³ and R¹⁴ is independentlyhalogen or C₁-C₆ alkyl. In certain such embodiments, both R¹³ and R¹⁴are halogen (e.g., fluoro or chloro). In certain such embodiments, eachof R⁷, R¹⁰ and R¹¹ is H. In certain such embodiments, each R⁸ and R⁹ isindependently C₁-C₆ alkyl, C₁-C₆ haloalkyl, optionally substituted C₃-C₇cycloalkyl, or optionally substituted (C₃-C₇ cycloalkyl)C₁-C₆ alkyl. Incertain such embodiments, each of R¹³ and R¹⁴ is independently halogen(e.g., chloro or fluoro); R⁸ is (C₃-C₇ cycloalkyl)C₁-C₆ alkyl (e.g.,—CH₂-cyclopropyl); and R⁹ is C₁-C₆ haloalkyl (e.g., —CF₃, —CHF₂, or—CH₂F). In certain embodiments, in Formula (II), (IIa), (IIb), (IIc), or(IId), R^(W) is

In one embodiment, provided herein is a compound of Formula (XLV):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R³,R⁷, R⁹, R¹⁰, R¹¹, R¹³, R¹⁴, R^(16b), R^(A), L¹, L², Q, Q¹, Q², Q³, X,and n are each as defined herein.

In another embodiment, provided herein is a compound of Formula (XLVI):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R³,R⁷, R⁹, R¹⁰, R¹¹, R¹³, R¹⁴, R^(16b), L¹, L², Q, and X are each asdefined herein.

In yet another embodiment, provided herein is a compound of Formula(XLVII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R⁹, R¹³,R¹⁴, L¹, L², and X are each as defined herein.

In still another embodiment, provided herein is a compound of Formula(XLVIII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R⁹, R¹³,R¹⁴, L², and X are each as defined herein.

In one embodiment, provided herein is a compound of Formula (XLIX):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R³,R⁷, R⁸, R¹⁰, R¹¹, R¹³, R¹⁴, R^(16b), R^(A), L¹, L², Q, Q¹, Q², Q³, X,and n are each as defined herein.

In another embodiment, provided herein is a compound of Formula (L):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R³,R⁷, R⁸, R¹⁰, R¹¹, R¹³, R¹⁴, R^(16b), L¹, L², Q, and X are each asdefined herein.

In yet another embodiment, provided herein is a compound of Formula(LI):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R⁸, R¹³,R¹⁴, L¹, L², and X are each as defined herein.

In still another embodiment, provided herein is a compound of Formula(LII):

or a diastereomer, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;wherein R⁸, R¹³, R¹⁴, L², and X are each as defined herein.

In one embodiment, provided herein is a compound of Formula (LIII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R³,R⁷, R⁹, R¹⁰, R¹¹, R¹³, R¹⁴, R^(16b), R^(A), L¹, L², Q, X, and n are eachas defined herein.

In one embodiment, provided herein is a compound of Formula (LIV):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R³,R⁷, R⁹, R¹⁰, R¹¹, R¹³, R¹⁴, R^(16b), R^(B), L¹, L², Q, and X are each asdefined herein.

In another embodiment, provided herein is a compound of Formula (LV):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R⁹, R¹³,R¹⁴, R^(B), L¹, L², and X are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula(LVI):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R⁹, R¹³,R¹⁴, R^(B), L², and X are each as defined herein.

In one embodiment, provided herein is a compound of Formula (LVII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R³,R⁷, R⁹, R¹⁰, R¹¹, R¹³, R¹⁴, R^(16b), R^(B), L¹, L², Q, and X are each asdefined herein.

In another embodiment, provided herein is a compound of Formula (LVIII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R⁹, R¹³,R¹⁴, R^(B), L¹, L², and X are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula(LIX):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R⁹, R¹³,R¹⁴, R^(B), L², and X are each as defined herein.

In one embodiment, provided herein is a compound of Formula (LX):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R³,R⁷, R⁸, R¹⁰, R¹¹, R¹³, R¹⁴, R^(16b), R^(A), L¹, L², Q, X, and n are eachas defined herein.

In one embodiment, provided herein is a compound of Formula (LXI):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R³,R⁷, R⁸, R¹⁰, R¹¹, R¹³, R¹⁴, R^(16b), R^(B), L¹, L², Q, and X are each asdefined herein.

In another embodiment, provided herein is a compound of Formula (LXII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R⁸, R¹³,R¹⁴, R^(B), L¹, L², and X are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula(LXIII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R⁸, R¹³,R¹⁴, L², and X are each as defined herein.

In one embodiment, provided herein is a compound of Formula (LXIV):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R³,R⁷, R⁸, R¹⁰, R¹¹, R¹³, R¹⁴, R^(16b), R^(B), L¹, L², Q, and X are each asdefined herein.

In another embodiment, provided herein is a compound of Formula (LXV):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R⁸, R¹³,R¹⁴, R^(B), L¹, L², and X are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula(LXVI):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R⁸, R¹³,R¹⁴, R^(B), L², and X are each as defined herein.

In one embodiment, provided herein is a compound of Formula (LXVII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R⁷, R⁹,R¹⁰, R¹¹, R¹³, R¹⁴, R^(2c), R^(2d), R^(16b), L¹, L², and X are each asdefined herein.

In another embodiment, provided herein is a compound of Formula(LXVIII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R⁹, R¹³,R¹⁴, L¹, L², and X are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula(LXIX):

or a diastereomer, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;wherein R⁹, R¹³, R¹⁴, L¹, L², and X are each as defined herein.

In one embodiment, provided herein is a compound of Formula (LXX):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R⁷, R⁸,R¹⁰, R¹¹, R¹³, R¹⁴, R^(2c), R^(2d), R^(16b), L¹, L², and X are each asdefined herein.

In another embodiment, provided herein is a compound of Formula (LXXI):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R⁸, R¹³,R¹⁴, L¹, L², and X are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula(LXXII):

or a diastereomer, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;wherein R⁸, R¹³, R¹⁴, L¹, L², and X are each as defined herein.

In certain embodiments, in any one of Formulae (XLV) to (LXXII), R⁸ isoptionally substituted C₁-C₆ alkyl, C₁-C₆ haloalkyl, or optionallysubstituted (C₃-C₇ cycloalkyl)C₁-C₆ alkyl. In certain embodiments, inany one of Formulae (XLV) to (LXXII), R⁸ is optionally substituted C₁-C₆alkyl. In certain embodiments, in any one of Formulae (XLV) to (LXXII),R⁸ is optionally substituted methyl. In certain embodiments, in any oneof Formulae (XLV) to (LXXII), R⁸ is methyl. In certain embodiments, inany one of Formulae (XLV) to (LXXII), R⁸ is C₁-C₆ haloalkyl. In certainembodiments, in any one of Formulae (XLV) to (LXXII), R⁸ isdifluoromethyl or trifluoromethyl. In certain embodiments, in any one ofFormulae (XLV) to (LXXII), R⁸ is optionally substituted (C₃-C₇cycloalkyl)C₁-C₆ alkyl. In certain embodiments, in any one of Formulae(XLV) to (LXXII), R⁸ is optionally substituted (C₃-C₇ cycloalkyl)methyl.In certain embodiments, in any one of Formulae (XLV) to (LXXII), R⁸ iscyclopropylmethyl.

In certain embodiments, in any one of Formulae (XLV) to (LXXII), R⁹ isoptionally substituted C₁-C₆ alkyl, C₁-C₆ haloalkyl, or optionallysubstituted (C₃-C₇ cycloalkyl)C₁-C₆ alkyl. In certain embodiments, inany one of Formulae (XLV) to (LXXII), R⁹ is optionally substituted C₁-C₆alkyl. In certain embodiments, in any one of Formulae (XLV) to (LXXII),R⁹ is optionally substituted methyl. In certain embodiments, in any oneof Formulae (XLV) to (LXXII), R⁹ is methyl. In certain embodiments, inany one of Formulae (XLV) to (LXXII), R⁹ is C₁-C₆ haloalkyl. In certainembodiments, in any one of Formulae (XLV) to (LXXII), R⁹ isdifluoromethyl or trifluoromethyl. In certain embodiments, in any one ofFormulae (XLV) to (LXXII), R⁹ is optionally substituted (C₃-C₇cycloalkyl)C₁-C₆ alkyl. In certain embodiments, in any one of Formulae(XLV) to (LXXII), R⁹ is optionally substituted (C₃-C₇ cycloalkyl)methyl.In certain embodiments, in any one of Formulae (XLV) to (LXXII), R⁹ iscyclopropylmethyl.

In certain embodiments, in any one of Formulae (XLV) to (LXXII), R¹³ ishalogen or optionally substituted C₁-C₆ alkyl. In certain embodiments,in any one of Formulae (XLV) to (LXXII), R¹³ is halogen. In certainembodiments, in any one of Formulae (XLV) to (LXXII), R¹³ is fluoro,chloro, or bromo. In certain embodiments, in any one of Formulae (XLV)to (LXXII), R¹³ is chloro. In certain embodiments, in any one ofFormulae (XLV) to (LXXII), R¹³ is optionally substituted C₁-C₆ alkyl. Incertain embodiments, in any one of Formulae (XLV) to (LXXII), R¹³ ismethyl or trifluoromethyl.

In certain embodiments, in any one of Formulae (XLV) to (LXXII), R¹⁴ ishalogen or optionally substituted C₁-C₆ alkyl. In certain embodiments,in any one of Formulae (XLV) to (LXXII), R¹⁴ is halogen. In certainembodiments, in any one of Formulae (XLV) to (LXXII), R¹⁴ is fluoro,chloro, or bromo. In certain embodiments, in any one of Formulae (XLV)to (LXXII), R¹⁴ is chloro. In certain embodiments, in any one ofFormulae (XLV) to (LXXII), R¹⁴ is optionally substituted C₁-C₆ alkyl. Incertain embodiments, in any one of Formulae (XLV) to (LXXII), R¹⁴ ismethyl or trifluoromethyl.

In certain embodiments, in any one of Formulae (XLV) to (LXXII), L¹, ifpresent, is a bond, —NH—, pyrrolidin-1,3-diyl, piperidin-1,3-diyl,piperidin-1,4-diyl,

In certain embodiments, in any one of Formulae (II) to (XIL), L¹, ifpresent, is a bond, —NH—, piperidin-1,4-diyl,

In certain embodiments, in any one of Formulae (XLV) to (LXXII), L² is abond, —O—, —NH—, or —C(═O)NH—.

In certain embodiments, in any one of Formulae (XLV) to (LXXII), X ispropan-1,3-diyl, butan-1,4-diyl, pentan-1,5-diyl, hexan-1,6-diyl,heptan-1,7-diyl, octan-1,8-diyl, nonan-1,9-diyl, decan-1,10-diyl,undecan-1,11-diyl, dodecan-1,12-diyl, hept-1-yn-1,7-diyl,

In certain embodiments, in any one of Formulae (XLV) to (LXXII), L¹, ifpresent, is a bond, —NH—, pyrrolidin-1,3-diyl, piperidin-1,3-diyl,piperidin-1,4-diyl,

L² is a bond, —O—, —NH—, or —C(═O)NH—; and X is propan-1,3-diyl,butan-1,4-diyl, pentan-1,5-diyl, hexan-1,6-diyl, heptan-1,7-diyl,octan-1,8-diyl, nonan-1,9-diyl, decan-1,10-diyl, undecan-1,11-diyl,dodecan-1,12-diyl, hept-1-yn-1,7-diyl,

In certain embodiments, in any one of Formulae (XLV) to (LXXII), L¹, ifpresent, is a bond, —NH—, piperidin-1,4-diyl,

L² is a bond, —O—NH—, or —C(═O)NH—; and X is propan-1,3-diyl,butan-1,4-diyl, pentan-1,5-diyl, hexan-1,6-diyl, heptan-1,7-diyl,octan-1,8-diyl, nonan-1,9-diyl, decan-1,10-diyl, undecan-1,11-diyl,dodecan-1,12-diyl, hept-1-yn-1,7-diyl,

In certain embodiments, in Formula (II), (IIa), (IIb), (IIc), or (IId),R^(W) is

wherein each R¹⁵ and R^(A) is as defined herein. In certain suchembodiments, each R^(A) is independently absent, halogen, or C₁-C₆alkyl. In certain such embodiments, R¹⁵ is H.

In certain embodiments, in Formula (II), (IIa), (IIb), (IIc), or (IId),R^(W) is

wherein R⁹, R¹⁰, R¹¹, R¹³, R¹⁴, and R^(16b) are each as defined herein.In certain such embodiments, each R¹³ and R¹⁴ is independently halogenor C₁-C₆ alkyl; and each R¹⁰ and R¹¹ is H. In certain such embodiments,each of R¹³ and R¹⁴ is independently halogen (e.g., chloro or fluoro);and R⁹ is C₁-C₆ alkyl (e.g., methyl or ethyl). In certain embodiments,R^(W) is

In certain embodiments, in Formula (II), R¹ is

and -L¹-X-L²- is one listed in Table A. In certain embodiments, inFormula (II), R¹ is

and -L¹-X-L²- is one listed in Table A; and R^(W) is as defined herein.

TABLE A —L¹—X—L²— —NH(CH₂)₂NHC(═O)(CH₂CH₂O)₃——NH(CH₂)₂NHC(═O)CH₂CH₂OCH₂CH₂— —NH(CH₂CH₂O)₃CH₂CH₂— —NH(CH₂CH₂O)₂CH₂CH₂——NH(CH₂CH₂O)₄— —NH(CH₂CH₂O)₃— —NH(CH₂)₁₋₃(OCH₂CH₂)₃——NH(CH₂)₁₋₃(OCH₂CH₂)₃O— —NH(CH₂)₁₋₃(OCH₂CH₂)₃—C(═O)— —NH(CH₂)₆O——NH(CH₂)₇O— —NH(CH₂)₈O— —O(CH₂)₂NHC(═O)(CH₂CH₂O)₃——O(CH₂)₂NHC(═O(CH₂CH₂O)₂CH₂CH₂— —O(CH₂)₂NHC(═O)CH₂CH₂OCH₂CH₂——CH₂NHC(O)NH(CH₂)₅NHC(O)CH₂—

—C(O)(CH₂)₄₋₁₀—O— —C(O)(CH₂)₆—O— —C(O)(CH₂)₈—O— —C(O)(CH₂)₁₀—O——C(O)(CH₂)₄₋₁₀— —C(O)(CH₂)₆— —C(O)(CH₂)₈— —C(O)(CH₂)₁₀—

—NH(CH₂)₂NHC(═O)(CH₂CH₂O)₂CH₂CH₂— —CH₂NHC(O)NH(CH₂)₇O—

In one embodiment, provided herein is:

-   8-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)octanamide    B1 (compound No. A);-   N-(6-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide    B2 (compound No. B);-   3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-N-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)benzamide    B3 (compound No. C);-   N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)oxy)benzamide    B4 (compound No. D);-   3-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)-4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile    B5 (compound No. E);-   2-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)-4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile    B6 (compound No. F);-   3-(4-(1-(7-((4-((3,5-dichloropyridin-4-yl)amino)-7-methoxy-2-oxo-2H-chromen-8-yl)oxy)heptyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione    B7 (compound No. G);-   3-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)propoxy)-ethoxy)ethoxy)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)propanamide    B8 (compound No. H);-   N-(6-(2-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)propoxy)-ethoxy)ethoxy)ethyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide    B9 (compound No. I);-   3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-N-(2-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)propoxy)ethoxy)ethoxy)-ethyl)benzamide    B10 (compound No. J);-   N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-(2-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)propoxy)ethoxy)ethoxy)ethoxy)benzamide    B11 (compound No. K);-   4-(2-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)propoxy)-ethoxy)ethoxy)ethyl)-3-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile    B12 (compound No. L);-   2-(2-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)propoxy)-ethoxy)ethoxy)ethyl)-4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile    B13 (compound No. M);-   3-(4-((3-(2-(2-(2-((4-((3,5-dichloropyridin-4-yl)amino)-7-methoxy-2-oxo-2H-chromen-8-yl)oxy)ethoxy)ethoxy)ethoxy)propyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione    B14 (compound No. N);-   6-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidin-1-yl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)-6-oxohexanamide    B15 (compound No. O);-   N-(6-(5-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidin-1-yl)-5-oxopentyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide    B16 (compound No. P);-   3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-N-(5-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidin-1-yl)-5-oxopentyl)benzamide    B17 (compound No. Q);-   N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((5-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidin-1-yl)-5-oxopentyl)oxy)benzamide    B18 (compound No. R);-   4-(5-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidin-1-yl)-5-oxopentyl)-3-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile    B19 (compound No. S);-   2-(5-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidin-1-yl)-5-oxopentyl)-4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile    B20 (compound No. T);-   3-(4-((1-(5-((4-((3,5-dichloropyridin-4-yl)amino)-7-methoxy-2-oxo-2H-chromen-8-yl)oxy)pentanoyl)piperidin-4-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione    B21 (compound No. U);-   8-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)piperidin-1-yl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)octanamide    B22 (compound No. V);-   N-(6-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide    B23 (compound No. W);-   3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-N-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)benzamide    B24 (compound No. X);-   N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)oxy)benzamide    B25 (compound No. Y);-   3-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)-4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile    B26 (compound No. Z);-   2-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)-4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile    B27 (compound No. AA);-   3-(4-(1-(7-((4-((3,5-dichloropyridin-4-yl)amino)-7-methoxy-2-oxo-2H-chromen-8-yl)oxy)heptyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione    B28 (compound No. AB);-   8-(4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)phenyl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)octanamide    B29 (compound No. AC);-   N-(6-(7-(4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)phenyl)heptyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide    B30 (compound No. AD);-   3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-N-(7-(4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)phenyl)-heptyl)benzamide    B31 (compound No. AE);-   N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-(4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)phenyl)heptyl)oxy)benzamide    B32 (compound No. AF);-   3-(7-(4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)phenyl)heptyl)-4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile    B33 (compound No. AG);-   2-(7-(4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)phenyl)heptyl)-4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile    B34 (compound No. AH);-   3-(1-((4-(7-((4-((3,5-dichloropyridin-4-yl)amino)-7-methoxy-2-oxo-2H-chromen-8-yl)oxy)heptyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione    B35 (compound No. AI);-   (2S,4R)-1-((S)-2-((8-((2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethyl)-1,3-dioxoisoindolin-4-yl)amino)-8-oxooctyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide    B36 (compound No. AJ);-   (2S,4R)-1-((S)-2-((7-(7-acetamido-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-5-yl)heptyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide    B37 (compound No. AK);-   (2S,4R)-1-((S)-2-((7-(3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamido)heptyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide    B38 (compound No. AL);-   (2S,4R)-1-((S)-2-((7-(5-((3,5-dichloropyridin-4-yl)carbamoyl)-2-(difluoromethoxy)-phenoxy)heptyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)-pyrrolidine-2-carboxamide    B39 (compound No. AM);-   (2S,4R)-1-((S)-2-((7-(5-cyano-2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)phenyl)heptyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide    B40 (compound No. AN);-   (2S,4R)-1-((S)-2-((7-(3-cyano-5-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)phenyl)heptyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide    B41 (compound No. AO); or-   (2S,4R)-1-((S)-2-((7-((4-((3,5-dichloropyridin-4-yl)amino)-7-methoxy-2-oxo-2H-chromen-8-yl)oxy)heptyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide    B42 (compound No. AP);    or an enantiomer, a mixture of enantiomers, a diastereomer, a    mixture of two or more diastereomers, a tautomer, a mixture of two    or more tautomers, or an isotopic variant thereof; or a    pharmaceutically acceptable salt, solvate, hydrate, or prodrug    thereof.

In another embodiment, provided herein is:

-   3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)-ethoxy)ethoxy)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)propanamide    B43;-   7-((4-((5-((S)-2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)benzyl)amino)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)heptanamide    B44;-   N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((9-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)nonyl)oxy)benzamide    B45;-   N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((5-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)pentyl)oxy)benzamide    B46;-   N-(6-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)hept-1-yn-1-yl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide    B47;-   14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)-3,6,9,12-tetraoxatetradecan-1-amide    B48;-   3-(6-fluoro-4-(1-(7-(2-methoxy-5-(1-oxoisoindolin-2-yl)phenoxy)heptyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione    B49;-   3-(4-(1-(7-(2-(cyclopentyloxy)-4-(1-oxoisoindolin-2-yl)phenoxy)heptyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione    B50;-   2-(3-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)oxy)-4-methoxyphenyl)isoindoline-1,3-dione    B51;-   5-amino-2-(3-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)oxy)-4-methoxyphenyl)isoindoline-1,3-dione    B52;-   3-(6-fluoro-4-(1-(7-(2-methoxy-5-(5-oxopyrrolidin-3-yl)phenoxy)heptyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione    B53;-   2-(3-(cyclopentyloxy)-4-methoxyphenyl)-5-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)amino)isoindoline-1,3-dione    B54;-   3-(6-fluoro-5-(1-(7-(2-methoxy-5-(5-oxopyrrolidin-3-yl)phenoxy)heptyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione    B55;-   3-(4-(1-(7-((2-(3-(cyclopentyloxy)-4-methoxyphenyl)-3-oxoisoindolin-5-yl)amino)heptyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione    B56;-   3-(4-(1-(7-(2-(cyclopentyloxy)-4-(5-oxopyrrolidin-3-yl)phenoxy)heptyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione    B57;-   5-amino-2-(3-(cyclopentyloxy)-4-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)oxy)phenyl)isoindoline-1,3-dione    B58;-   2-(3-(cyclopentyloxy)-4-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)oxy)phenyl)isoindoline-1,3-dione    B59;-   3-(4-(1-(7-(5-(6-amino-1-oxoisoindolin-2-yl)-2-methoxyphenoxy)heptyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione    B60;-   N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperidin-1-yl)heptyl)oxy)benzamide    B61;-   3-(4-(1-(7-(5-(6-amino-1-oxoisoindolin-2-yl)-2-methoxyphenoxy)heptyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione    B62;-   N¹-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)-N¹⁰-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)decanediamide    B63;-   3-((4-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)-methyl)benzyl)oxy)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)propanamide    B64;-   5-(3-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)oxy)-4-methoxyphenyl)-4H-thieno[2,3-c]pyrrole-4,6(5H)-dione    B65;-   2-(2,6-dioxopiperidin-3-yl)-4-((7-(2-methoxy-5-(5-oxopyrrolidin-3-yl)phenoxy)-heptyl)amino)isoindoline-1,3-dione    B66;-   (2S,4R)-4-hydroxy-1-((2S)-2-(9-(2-methoxy-5-(5-oxopyrrolidin-3-yl)phenoxy)-nonanamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide    B67;-   (2S,4R)-1-((S)-2-(9-(5-((3,5-dichloropyridin-4-yl)carbamoyl)-2-(difluoromethoxy)phenoxy)nonanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide    B68;-   N-(6-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)propyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide    B69;-   9-((4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)benzyl)amino)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)nonanamide    B70;-   12-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)dodecanamide    B71;-   N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptyl)oxy)benzamide    B72;-   N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((12-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)dodecyl)oxy)benzamide    B73;-   N-(3,5-dichloropyridin-4-yl)-3-(difluoromethoxy)-4-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)ethoxy)benzamide    B74;-   9-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperidin-1-yl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)nonanamide    B75;-   (2S,4R)-1-((S)-2-(11-(5-((3,5-dichloropyridin-4-yl)carbamoyl)-2-(difluoromethoxy)-phenoxy)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide    B76;-   9-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)nonanamide    B77;-   5-((4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)benzyl)amino)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)pentanamide    B78;-   N-(6-(12-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)dodecyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide    B79;-   3-(6-fluoro-4-(1-(7-(2-methoxy-5-(4-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)phenoxy)heptyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione    B80;-   3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(2-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)propoxy)ethoxy)ethoxy)ethoxy)benzamide    B81;-   3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)oxy)benzamide    B82;-   N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)propoxy)benzamide    B83;-   3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-((9-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)nonyl)oxy)benzamide    B84;-   3-((9-(4-(2-(1-acetamido-1-oxopropan-2-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)nonyl)oxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide    B85;-   (2S,4R)-1-((S)-2-(9-(2-(cyclopropylmethoxy)-5-((3,5-dichloropyridin-4-yl)carbamoyl)phenoxy)nonanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide    B86;-   5-(3-(cyclopentyloxy)-4-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)oxy)phenyl)-4H-thieno[2,3-c]pyrrole-4,6(5H)-dione    B87;-   N-(6-(7-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)heptyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide    B88;-   3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)propanamide    B89;-   N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)heptyl)oxy)benzamide    B90;-   3-(4-(1-(7-(2-(cyclopentyloxy)-4-(4-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)phenoxy)heptyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione    B91; or-   N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-((4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)benzyl)amino)heptyl)oxy)benzamide    B92;    or an enantiomer, a mixture of enantiomers, a diastereomer, a    mixture of two or more diastereomers, a tautomer, a mixture of two    or more tautomers, or an isotopic variant thereof; or a    pharmaceutically acceptable salt, solvate, hydrate, or prodrug    thereof.

In certain embodiments, a compound provided herein is isolated orpurified. In certain embodiments, a compound provided herein has apurity of at least about 90%, at least about 95%, at least about 98%, atleast about 99%, or at least about 99.5% by weight.

The compounds provided herein are intended to encompass all possiblestereoisomers, unless a particular stereochemistry is specified. Where acompound provided herein contains an alkenyl group, the compound mayexist as one or mixture of geometric cis/trans (or Z/E) isomers. Wherestructural isomers are interconvertible, the compound may exist as asingle tautomer or a mixture of tautomers. This can take the form ofproton tautomerism in the compound that contains, for example, an imino,keto, or oxime group; or so-called valence tautomerism in the compoundthat contains an aromatic moiety. It follows that a single compound mayexhibit more than one type of isomerism.

A compound provided herein can be enantiomerically pure, such as asingle enantiomer or a single diastereomer, or be stereoisomericmixtures, such as a mixture of enantiomers, e.g., a racemic mixture oftwo enantiomers; or a mixture of two or more diastereomers. As such, oneof ordinary skill in the art will recognize that administration of acompound in its (R) form is equivalent, for the compound that undergoesepimerization in vivo, to administration of the compound in its (S)form. Conventional techniques for the preparation/isolation ofindividual enantiomers include synthesis from a suitable optically pureprecursor, asymmetric synthesis from achiral starting materials, orresolution of an enantiomeric mixture, for example, chiralchromatography, recrystallization, resolution, diastereomeric saltformation, or derivatization into diastereomeric adducts followed byseparation.

When a compound provided herein contains an acidic or basic moiety, itcan also be provided as a pharmaceutically acceptable salt. See, Bergeet al., J. Pharm. Sci. 1977, 66, 1-19; Handbook of Pharmaceutical Salts:Properties, Selection, and Use, 2nd ed.; Stahl and Wermuth Eds.; JohnWiley & Sons, 2011. In certain embodiments, a pharmaceuticallyacceptable salt of a compound provided herein is a solvate. In certainembodiments, a pharmaceutically acceptable salt of a compound providedherein is a hydrate.

Suitable acids for use in the preparation of pharmaceutically acceptablesalts of a compound provided herein include, but are not limited to,acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid,alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid,benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid,camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid,caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid,cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxoglutaric acid,glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid,hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionicacid, lauric acid, maleic acid, (−)-L-malic acid, malonic acid,(±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinicacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid,saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid,stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaricacid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, andvaleric acid.

Suitable bases for use in the preparation of pharmaceutically acceptablesalts of a compound provided herein include, but are not limited to,inorganic bases, such as magnesium hydroxide, calcium hydroxide,potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organicbases, such as primary, secondary, tertiary, and quaternary, aliphaticand aromatic amines, including, but not limited to, L-arginine,benethamine, benzathine, choline, deanol, diethanolamine, diethylamine,dimethylamine, dipropylamine, diisopropylamine,2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine,isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine,morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine,piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine,pyridine, quinuclidine, quinoline, isoquinoline, triethanolamine,trimethylamine, triethylamine, N-methyl-D-glucamine,2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.

A compound provided herein may also be provided as a prodrug, which is afunctional derivative of the compound and is readily convertible intothe parent compound in vivo. Prodrugs are often useful because, in somesituations, they may be easier to administer than the parent compound.They may, for instance, be bioavailable by oral administration whereasthe parent compound is not. The prodrug may also have enhancedsolubility in pharmaceutical compositions over the parent compound. Aprodrug may be converted into the parent drug by various mechanisms,including enzymatic processes and metabolic hydrolysis.

Uses or Methods of Treatment

In one embodiment, provided herein is a method of treating, preventing,or ameliorating one or more symptoms of a disease, disorder, orcondition associated with a PDE4 in a subject, comprising administeringto the subject in need thereof a therapeutically effective amount of acompound of Formula (I) or (II), or a pharmaceutically acceptable saltthereof.

In certain embodiments, the disease, disorder, or condition associatedwith a PDE4 is an inflammatory disease.

In certain embodiments, the PDE4 is a PDE4A. In certain embodiments, thePDE4 is a PDE4B. In certain embodiments, the PDE4 is a PDE4C. In certainembodiments, the PDE4 is a PDE4D. In certain embodiments, the PDE4 is aPDE4D. In certain embodiments, the PDE4 is a PDE4D short isoform.

In another embodiment, provided herein is a method of treating,preventing, or ameliorating one or more symptoms of an inflammatorydisease in a subject, comprising administering to the subject in needthereof a therapeutically effective amount of a compound of Formula (I)or (II), or a pharmaceutically acceptable salt thereof.

In certain embodiments, the inflammatory disease is arthritis,ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, Behcet'sdisease, an inflammatory bowel disease, Crohn's disease, ulcerativecolitis, psoriasis, psoriatic arthritis, atopic dermatitis, contactdermatitis, or COPD. In certain embodiments, the inflammatory disease ispsoriasis. In some embodiments, the inflammatory disease is psoriaticarthritis. In certain embodiments, the inflammatory disease is atopicdermatitis. In certain embodiments, the inflammatory disease is contactdermatitis.

In yet another embodiment, provided herein is a method of treating,preventing, or ameliorating one or more symptoms of psoriasis, psoriaticarthritis, or atopic dermatitis in a subject, comprising administeringto the subject in need thereof a therapeutically effective amount of acompound of Formula (I) or (II), or a pharmaceutically acceptable saltthereof.

In certain embodiments, the subject is a mammal. In certain embodiments,the subject is a human.

In yet another embodiment, provided herein is a method of inhibiting theactivity of a phosphodiesterase 4 (PDE4), comprising contacting the PDE4with an effective amount of a compound of Formula (I) or (II), or apharmaceutically acceptable salt thereof.

In certain embodiments, the PDE4 is a PDE4A. In certain embodiments, thePDE4 is a PDE4B. In certain embodiments, the PDE4 is a PDE4C. In certainembodiments, the PDE4 is a PDE4D. In certain embodiments, the PDE4 is aPDE4D. In certain embodiments, the PDE4 is a PDE4D short isoform.

In still another embodiment, provided herein is a method of decreasingexpression of a protein selected from TNF-α, INF-γ, IL-2, IL-17, andIL-23, comprising contacting the protein with an effective amount of acompound of Formula (I) or Formula (II), or a pharmaceuticallyacceptable salt thereof. In certain embodiments, the protein is TNF-α.

Dosing Regimes

In certain embodiments, therapeutically effective amount is ranging fromabout 1 mg to about 5 grams; from about 2 mg to about 2 gram; from about5 mg to about 1 gram; from about 10 mg to about 800 mg; from about 20 mgto about 600 mg; from about 30 mg to about 400 mg; from about 40 mg toabout 200 mg; from about 50 mg to about 100 mg of a compound providedherein each day. In certain embodiments, therapeutically effectiveamount is ranging from about 1 mg to about 5 grams; from about 2 mg toabout 2 gram; from about 5 mg to about 1 gram; from about 10 mg to about800 mg; from about 20 mg to about 600 mg; from about 30 mg to about 400mg; from about 40 mg to about 200 mg; from about 50 mg to about 100 mgof a compound provided herein each day each week. In certainembodiments, from about 1 mg to about 5 grams; from about 2 mg to about2 gram; from about 5 mg to about 1 gram; from about 10 mg to about 800mg; from about 20 mg to about 600 mg; from about 30 mg to about 400 mg;from about 40 mg to about 200 mg; from about 50 mg to about 100 mg of acompound provided herein each cycle of treatment.

In certain embodiments, a compound provided herein is administered atleast once per day, at least twice per day, at least three times perday, or at least four times per day. In certain embodiments, each cycleof treatment lasts 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14days. In certain embodiments, each cycle of treatment has at least 1, 2,3, 4, 5, 6, or 7 days between administrations of a compound providedherein.

Pharmaceutical Compositions

In certain embodiments, provided herein is a pharmaceutical composition,comprising a compound provided herein, or an enantiomer, a mixture ofenantiomers, a diastereomer, a mixture of two or more diastereomers, atautomer, a mixture of two or more tautomers, or an isotopic variantthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof; and a pharmaceutically acceptable carrier or excipient.

In certain embodiments, a pharmaceutical composition provided herein isformulated for intravenous injection, subcutaneous injection, oraladministration, buccal administration, inhalation, nasal administration,topical administration, transdermal administration, ophthalmicadministration, or otic administration. In certain embodiments, apharmaceutical composition provided herein is formulated in the form ofa tablet, a pill, a capsule, a liquid, an inhalant, a nasal spraysolution, a suppository, a suspension, a gel, a colloid, a dispersion, asolution, an emulsion, an ointment, a lotion, an eye drop, or an eardrop.

In certain embodiments, a pharmaceutical composition provided herein isformulated as a gel, salve, ointment, cream, emulsion, or paste fortopical application to the skin. In certain embodiments, apharmaceutical composition provided herein is formulated for oraladministration.

The disclosure will be further understood by the following non-limitingexamples.

EXAMPLES

As used herein, the symbols and conventions used in these processes,schemes and examples, regardless of whether a particular abbreviation isspecifically defined, are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety, the Journal of Medicinal Chemistry, or the Journal ofBiological Chemistry. Specifically, but without limitation, thefollowing abbreviations may be used in the examples and throughout thespecification: g (grams); mg (milligrams); mL (milliliters); μL(microliters); mM (millimolar); μM (micromolar); mmol (millimoles); h(hour or hours); min (minute or minutes); ACN (acetonitrile); AcOH(acetic acid); DCM (dichloromethane); DMF (dimethylformamide); DMSO(dimethyl sulfoxide); EtOH (ethanol); MeOH (methanol); EtOAc (ethylacetate); PE (petroleum ether); THF (tetrahydrofuran); Ac₂O (aceticanhydride); CDI (1,1′-carbonyldiimidazole); DIBAL-H (diisobutylaluminumhydride); DIPEA (N,N-diisopropylethylamine); HATU(1-(bis(dimethylamino)methylene)-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate); HOBt (1-hydroxybenzotriazole); TEA(triethylamine); TFA (trifluoroacetic acid); HPLC (high-performanceliquid chromatography); MS (mass spectrometry); NMR (nuclear magneticresonance); and TLC (thin-layer chromatography).

For all of the following examples, standard work-up and purificationmethods known to those skilled in the art can be utilized. Unlessotherwise indicated, all temperatures are expressed in ° C. (degreesCentigrade). All reactions are conducted at room temperature unlessotherwise specified. Synthetic methodologies illustrated herein areintended to exemplify the applicable chemistry through the use ofspecific examples and are not indicative of the scope of the disclosure.

Example 1 Synthesis of(S)-1-Amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione

A solution of thiophene-3,4-dicarboxylic acid (25.0 g, 145 mmol) in Ac₂O(250 mL) was heated to 110° C. for 16 h. The mixture was thenconcentrated to give thieno[3,4-c]-furan-1,3-dione (22.0 g, crude) as asolid.

Thieno[3,4-c]furan-1,3-dione (22.0 g, 143 mmol) was added to nitric acid(95%, 90 mL) over 1 h at 0-5° C. After stirred at room temperature for 1h, the reaction mixture was poured into ice water and extracted withEtOAc. The combined organic layers were dried over anhydrous Na₂SO₄,filtered, and concentrated to give 2-nitrothiophene-3,4-dicarboxylicacid (20.8 g) in 66% yield as a solid.

A solution of 2-nitrothiophene-3,4-dicarboxylic acid (6.0 g, 27.6 mmol)in Ac₂O (60 mL) was heated to 140° C. for 3 h. The mixture wasconcentrated to give 4-nitrothieno[3,4-c]-furan-1,3-dione (5.5 g, crude)as a solid.

A mixture of 4-nitrothieno[3,4-c]furan-1,3-dione (5.5 g, 27.64 mmol) and(S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine (7.54 g,27.64 mmol) in THF (250 mL) was stirred at room temperature for 16 h.CDI (5.37 g, 33.1 mmol) was then added. After refluxed for 3 h, themixture was concentrated and purified on silica gel eluting withEtOAc/PE from 30% to 50% to give(S)-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1-nitro-4H-thieno[3,4-c]-pyrrole-4,6(5H)-dione(10.0 g) in 79% yield as a solid.

A mixture of(S)-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1-nitro-4H-thieno[3,4-c]-pyrrole-4,6(5H)-dione(1.0 g, 2.2 mmol), ammonium chloride (706 mg, 13.2 mmol), and ironpowder (740 mg, 13.2 mmol) in THF/water (50 mL/10 mL) was refluxed for 1h. The mixture was then filtered, concentrated, and purified on silicagel eluting with EtOAc/PE from 40% to 70% to give(S)-1-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione(Intermediate 1) (300 mg) in 32% yield as a solid. MS (ESI) m/z: 424.9[M+H]⁺.

The following compounds were prepared similarly.

-   (S)-1-Amino-5-(1-(3-cyclopropoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione.-   (R)-1-Amino-5-(1-(3-cyclopropoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione.

-   (S)-1-Amino-5-(1-(3-cyclopropoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione.-   (R)-1-Amino-5-(1-(3-cyclopropoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione.

Example 2 Synthesis of(S)-3-Amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[2,3-c]pyrrol-6(5H)-one

To a stirred solution of methyl4-bromo-3-(bromomethyl)thiophene-2-carboxylate (628 mg, 2 mmol) and(S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine (819 mg,3.0 mmol) in ACN (20 mL) was added Cs₂CO₃ (358 mg, 1.1 mmol). Afterstirred at room temperature overnight, the mixture was concentrated andpurified on silica gel eluting with EtOAc/PE (1:1) to give(S)-methyl-4-bromo-3-(((1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)amino)-methyl)thiophene-2-carboxylate(905 mg) in 90% yield as a solid. MS (ESI) m/z: 505.9 [M+H]⁺.

To a stirred solution of(S)-methyl-4-bromo-3-(((1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)amino)methyl)thiophene-2-carboxylate(740 mg, 1.46 mmol) in THF (8 mL) and MeOH (8 mL) was added a solutionof lithium hydroxide (614 mg, 14.6 mmol) in water (8 mL). After stirredat room temperature for 8 h, the mixture was concentrated, acidified topH 4 with 2 N HCl, and then extracted with DCM. The combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄, andconcentrated to give(S)-4-bromo-3-(((1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)amino)methyl)thiophene-2-carboxylicacid (638 mg) in 89% yield as a solid. MS (ESI) m/z: 491.9 [M+H]⁺.

To a stirred solution of(S)-4-bromo-3-(((1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)amino)methyl)thiophene-2-carboxylicacid (628 mg, 1.27 mmol) in DCM (20 mL) was added oxalyl chloride (486mg, 3.8 mmol) dropwise, followed by addition of 2 drops of DMF. Themixture was stirred at room temperature overnight, and then concentratedand purified on silica gel eluting with DCM/MeOH (10:1) to give(S)-4-bromo-5-(1-(3-ethoxy-4-methoxy-phenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[2,3-c]pyrrol-6(5H)-one(398 mg) in 66% yield as a solid. MS (ESI) m/z: 473.9 [M+H]⁺.

To a stirred solution of(S)-4-bromo-5-(1-(3-ethoxy-4-methoxy-phenyl)-2-(methyl-sulfonyl)ethyl)-4H-thieno[2,3-c]pyrrol-6(5H)-one(364 mg, 0.77 mmol) and diphenylmethanimine (183 mg, 1.01 mmol) in1,4-dioxane (3.5 mL) and toluene (3.5 mL) were added Cs₂CO₃ (511 mg,1.56 mmol), tris(dibenzylideneacetone)dipalladium (73 mg, 0.08 mmol),and Xantphos (110 mg, 0.21 mmol). After N₂ purge and stirred at 108° C.(microwave) for 16 h, the mixture was diluted with water and EtOAc. Theorganic layer was separated, washed with brine, dried over anhydrousNa₂SO₄, filtered, concentrated, and purified using prep-TLC eluting withpetroleum/EtOAc (1:1) to give(S)-4-((diphenylmethylene)amino)-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[2,3-c]pyrrol-6(5H)-one(140 mg) in 32% yield as a solid. MS (ESI) m/z: 575.0 [M+H]⁺.

To a stirred solution of(S)-4-((diphenylmethylene)amino)-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[2,3-c]pyrrol-6(5H)-one(140 mg, 0.24 mmol) in EtOAc (5 mL) was added a solution of HCl in EtOAc(2.5 mL). The mixture was stirred at room temperature for 20 min, andthen concentrated and washed with petroleum to give(S)-4-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[2,3-c]pyrrol-6(5H)-one(Intermediate 2) (130 mg, crude) as a solid, which was used directlywithout further purification. MS (ESI) m/z: 411.0 [M+H]⁺.

Example 3 Synthesis of(S)-N-(5-(1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-2,2,2-trifluoroacetamideA1

To a solution of Intermediate 1 (100 mg, 0.236 mmol) in pyridine (5 mL)was added trifluoroacetic anhydride (0.2 mL) in ACN (1 mL) at 0° C.After stirred at room temperature for 4 h, the mixture was diluted withwater and then extracted with EtOAc. The combined organic layers werewashed with HCl (1N), dried over anhydrous Na₂SO₄, filtered,concentrated, and purified on silica gel eluting with EtOAc/PE from 40%to 70% to give compound A1 (19 mg) in 16% yield as a white solid. MS(ESI) m/z: 520.5 [M+H]⁺.

The following compounds were prepared similarly according to thesynthetic procedures or methodologies exemplified herein.

-   (S)-N-(5-(1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)-2-methoxyacetamide    A2. MS (ESI) m/z: 483.1 [M+H]⁺.-   (S)-N-(5-(1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)cyclopropanecarboxamide    A3. MS (ESI) m/z: 479.1 [M+H]⁺.

-   (S)-N-(5-(1-(3-Cyclopropoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)acetamide    A4. MS (ESI) m/z: 479.1 [M+H]⁺.-   (R)-N-(5-(1-(3-Cyclopropoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)acetamide    A5. MS (ESI) m/z: 478.9 [M+H]⁺.-   (S)-N-(5-(2-(Cyclopropylsulfonyl)-1-(3-ethoxy-4-methoxyphenyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)acetamide    A6. MS (ESI) m/z: 493.0 [M+H]⁺.

(S)-N-(5-(2-(Cyclopropylsulfonyl)-1-(3-ethoxy-4-methoxyphenyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-2,2,2-trifluoroacetamideA7. MS (ESI) m/z: 546.6 [M+H]⁺.

-   (R)-N-(5-(2-(Cyclopropylsulfonyl)-1-(3-ethoxy-4-methoxyphenyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-2,2,2-trifluoroacetamide    A8. MS (ESI) m/z: 546.8 [M+H]⁺.-   (R)-N-(5-(2-(Cyclopropylsulfonyl)-1-(3-ethoxy-4-methoxyphenyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-2-methoxyacetamide    A9. MS (ESI) m/z: 523.0 [M+H]⁺.

-   (R)-N-(5-(2-(Cyclopropylsulfonyl)-1-(3-ethoxy-4-methoxyphenyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)acetamide    A10. MS (ESI) m/z: 493.0 [M+H]⁺.-   (S)-N-(5-(2-(Cyclopropylsulfonyl)-1-(3-ethoxy-4-methoxyphenyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-2-methoxyacetamide    A11. MS (ESI) m/z: 523.1 [M+H]⁺.

Example 4 Synthesis ofN-(6-(7-(4-(2-(2,6-Dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamideB2 andN-(6-(7-(4-(2-(2,6-Dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)hept-1-yn-1-yl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamideB47

To a solution of 2-methyl-3-nitrobenzoic acid (5.00 g, 27.6 mmol) inH₂SO₄ (25 mL) at 60° C. was added N-iodosuccinimide (7.458 g, 33.1 mmol)in portions. The mixture was stirred at 60° C. for 2 h and then pouredinto 150 g of ice. The mixture was filtered, washed with water andpetroleum ether, and concentrated to afford5-iodo-2-methyl-3-nitrobenzoic acid (8.302 g) in 98% yield. MS (ESI)m/z: 306.2 [M−H]⁻.

To a suspension of 5-iodo-2-methyl-3-nitrobenzoic acid (3.0 g, 10 mmol)in water (78 mL) was added NaOH (2M solution, 5.2 mL, 2.6 mmol),followed by addition of KMnO₄ (6.32 g, 40 mmol) at 60° C. After refluxedovernight, the mixture was cooled to 80° C., filtered, and washed withhot water. The filtrate was acidified to pH 1 with conc. HCl, filtered,and concentrated to afford 5-iodo-3-nitrophthalic acid (5.2 g) in aquantitative yield. MS (ESI) m/z: 335.9 [M−H]⁻.

A solution of 5-iodo-3-nitrophthalic acid (5.2 g, 10 mmol) in aceticanhydride (20 mL) was heated to 140° C. and stirred for 3 h. The mixturewas concentrated to give 6-iodo-4-nitroisobenzofuran-1,3-dione (5.0 g,crude).

To a solution of 6-iodo-4-nitroisobenzofuran-1,3-dione (5.0 g, crude) inacetic acid (20 mL) was added(S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine (4.1 g, 15mmol). After stirred at 60° C. for 3 h, the mixture was concentrated andwater/EtOH (4:1) was added. The resulting solid was collected byfiltration and washed with petroleum ether to afford(S)-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-6-iodo-4-nitroisoindoline-1,3-dione(2.3 g) in 40% yield. MS (ESI) m/z: 574.9 [M+H]⁺.

To a solution of(S)-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-6-iodo-4-nitroisoindoline-1,3-dione(2.3 g, 4 mmol) in EtOH (40 mL) and water (20 mL) were added NH₄Cl (1.08g, 20 mmol) and iron powder (1.12 g, 20 mmol). After refluxed for 1 h,the mixture was filtered through celite, washed with ethyl acetate,concentrated, and purified using silica gel eluting with methanol indichloromethane from 0% to 5% to give(S)-4-amino-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-6-iodoisoindoline-1,3-dione(1.366 g) in 63% yield. MS (ESI) m/z: 562.2 [M+NH₄]⁺.

To a solution of(S)-4-amino-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethyl)-6-iodoisoindoline-1,3-dione(1.366 g, 2.5 mmol) in dichloromethane (10 mL) were added triethylamine(0.7 mL, 5 mmol) and acetyl chloride (234 mg, 3 mmol) at 0° C. Themixture was stirred at room temperature for 3 h and then concentrated.The residue was purified using silica gel eluting with ethyl acetate inpetroleum ether from 50% to 85% to give(S)-N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-6-iodo-1,3-dioxoisoindolin-4-yl)acetamide(700 mg) in 48% yield. MS (ESI) m/z: 587.5 [M+H]⁺.

To a solution of(S)-N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-6-iodo-1,3-dioxoisoindolin-4-yl)acetamide(450 mg, 0.77 mmol) and3-(6-fluoro-4-(1-(hept-6-yn-1-yl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(828 mg, 1.89 mmol) in N,N-dimethylformamide (10 mL) were addedPd(PPh₃)₂Cl₂ (112 mg, 0.16 mmol), CuI (30 mg, 0.16 mmol), andtriethylamine (191 mg, 1.89 mmol) under N₂. After the mixture wasstirred at 80° C. for 5 h, 1N HCl was added and the mixture wasextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄, filtered, and concentrated. Theresidue was purified using silica gel eluting with methanol indichloromethane from 3% to 10% and further purified using prep-HPLC toaffordN-(6-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)hept-1-yn-1-yl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamideB47 (45 mg) in 7% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 11.02 (s, 1H), 9.70(s, 1H), 8.44 (s, 1H), 7.49 (s, 1H), 7.36 (d, J=8.8 Hz, 2H), 7.06 (s,1H), 6.98-6.90 (m, 2H), 5.79-5.73 (m, 1H), 5.14 (dd, J=4.4, 12.4 Hz,1H), 4.53-4.28 (m, 3H), 4.17-4.12 (m, 1H), 4.01 (q, J=7.6 Hz, 2H), 3.73(s, 3H), 3.01 (s, 3H), 2.97-2.54 (m, 2H), 2.67-2.54 (m, 2H), 2.43-2.32(m, 2H), 2.19 (s, 3H), 2.03-1.95 (m, 3H), 1.80-1.73 (m, 4H), 1.65-1.45(m, 6H), 1.32 (t, J=6.0 Hz, 3H), 1.26-1.21 (m, 4H); MS (ESI) m/z: 898.3[M+H]⁺.

To a solution ofN-(6-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)hept-1-yn-1-yl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide(50 mg, 0.06 mmol) in THF (3 mL) and MeOH (3 mL) was added Pd/C (5 mg,0.04 mmol). After stirred under H₂ for 20 h, the mixture was filteredand washed with ethyl acetate. The filtrate was concentrated and theresidue was purified using prep-HPLC to affordN-(6-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamideB2 (12 mg) in 24% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 11.01 (s, 1H), 9.64(s, 1H), 8.28 (s, 1H), 7.46-7.31 (m, 3H), 7.06 (s, 1H), 6.98-6.90 (m,2H), 5.76 (dd, J=4.0, 10.4 Hz, 1H), 5.13 (dd, J=5.2, 13.2 Hz, 1H),4.52-4.31 (m, 3H), 4.15-4.10 (m, 1H), 4.01(q, J=6.8 Hz, 2H), 3.73 (s,3H), 3.01 (s, 3H), 2.96-2.89 (m, 3H), 2.76-2.65 (m, 2H), 2.64-2.54 (m,2H), 2.46-2.39 (m, 1H), 2.29-2.21 (m, 2H), 2.18 (s, 3H), 2.06-1.86 (m,4H), 1.78-1.64 (m, 4H), 1.63-1.52 (m, 2H), 1.46-1.36 (m, 2H), 1.35-1.18(m, 8H); MS (ESI) m/z: 902.3 [M+H]⁺.

Example 5 Synthesis ofN-(3,5-Dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)oxy)benzamideB4

To a solution of methyl 4-(difluoromethoxy)-3-hydroxybenzaldehyde (1.0g, 5.32 mmol) in ACN (14 mL) were added K₂CO₃ (2.20 g, 15.96 mmol) and7-iodo-N-methoxy-N-methylheptanamide (2.39 g, 7.92 mmol). After stirredat 80° C. for 2 h, the mixture was diluted with H₂O and extracted withEtOAc. The combined organic layers were dried over anhydrous Na₂SO₄,filtered, and concentrated. The residue was purified using silica gelwith ethyl acetate in petroleum ether from 0% to 50% to give7-(2-(difluoromethoxy)-5-formylphenoxy)-N-methoxy-N-methylheptanamide(1.8 g) in 94% yield. MS (ESI) m/z: 360.3 [M+H]⁺.

To a solution of7-(2-(difluoromethoxy)-5-formylphenoxy)-N-methoxy-N-methylheptanamide(1.8 g, 5.01 mmol) in acetic acid (40 mL) were added sulfamic acid (1.46g, 15.04 mmol) and a solution of sodium chlorite (1.36 g, 15.04 mmol) inH₂O (13 mL) dropwise. After stirred at 35° C. for 2 h, the mixture wasdiluted with H₂O and filtered to give4-(difluoromethoxy)-3-((7-(methoxy(methyl)amino)-7-oxoheptyl)oxy)benzoicacid (1.88 g) in 90% yield. MS (ESI) m/z: 376.3 [M+H]⁺.

To a solution of4-(difluoromethoxy)-3-((7-(methoxy(methyl)amino)-7-oxoheptyl)oxy)benzoicacid (500 mg, 1.333 mmol) in dichloromethane (8 mL) in 0° C. were addedoxalyl chloride (250 mg, 2.00 mmol) and DMF (1 drop). After stirred atroom temperature for 1 h, the mixture was concentrated to give4-(difluoromethoxy)-3-((7-(methoxy(methyl)amino)-7-oxoheptyl)oxy)benzoylchloride (crude).

To a solution of 3,5-dichloropyridin-4-amine (464 mg, 2.67 mmol) intetrahydrofuran (6 mL) in 0° C. was added sodium hydride (64 mg, 2.67mmol). After the mixture was stirred at 0° C. for 30 min,N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-(methoxy(methyl)amino)-7-oxoheptyl)oxy)benzamide(524 mg, 1.33 mmol) was added. After stirred at room temperature for 2h, the mixture was diluted with H₂O and extracted with ethyl acetate.The combined organic layers were dried over anhydrous Na₂SO₄, filtered,and concentrated. The residue was purified using silica gel eluting withethyl acetate in petroleum ether from 0% to 40% to giveN-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-(methoxy(methyl)amino)-7-oxoheptyl)oxy)-benzamide(254 mg) in 37% yield. MS (ESI) m/z: 520.1 [M+H]⁺.

To a solution ofN-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-(methoxy(methyl)amino)-7-oxoheptyl)oxy)benzamide(50 mg, 0.096 mmol) in tetrahydrofuran (3 mL) at −78° C. under nitrogenwas added lithium aluminum hydride (0.14 mL, 1M in tetrahydrofuran)dropwise. After stirred at this temperature for 1 h, the reaction wasquenched with ammonium chloride (5 mL) and the reaction mixture wasextracted with ethyl acetate. The combined organic layers were driedover anhydrous sodium sulfate, filtered, and concentrated to giveN-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-oxoheptyl)oxy)benzamide(40 mg, crude). MS (ESI) m/z: 461.1[M+H]⁺.

To a solution of3-(6-fluoro-1-oxo-4-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione(42 mg, 0.010 mmol) in dichloromethane/methanol (4 mL/1 mL) was addedN,N-diisopropylethylamine (12 mg, 0.10 mmol) at 0° C., followed byaddition ofN-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-oxoheptyl)oxy)benzamide(40 mg, crude, 0.10 mmol), NaBH₃CN (12 mg, 0.19 mmol), and acetic acid(1 drop). The mixture was stirred at room temperature overnight and thenconcentrated. The residue was purified using prep-HPLC eluting withwater (0.1% TFA) in ACN (0.1% TFA) at a gradient of 95 to 5% to giveN-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)oxy)benzamideB4 (17.2 mg) in 23% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 11.00 (s, 1H),10.66 (brs, 1H), 8.77 (s, 2H), 7.73 (d, J=2.0 Hz, 1H), 7.66 (dd, J=2.0,8.4 Hz, 1H), 7.40-7.07 (m, 4H), 5.14 (dd, J=4.8, 13.2 Hz, 1H), 4.53-4.32(m, 2H), 4.13 (t, J=6.4 Hz, 2H), 3.52-3.49 (m, 2H), 3.01-2.88 (m, 3H),2.62-2.58 (m, 2H), 2.45-2.35 (m, 2H), 2.07-1.99 (m, 3H), 1.81-1.70 (m,5H), 1.51-1.27 (m, 8H); MS (ESI) m/z: 790.3 [M+H]⁺.

Example 6 Synthesis ofN-(6-(5-(4-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidin-1-yl)-5-oxopentyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamideB16

To a solution of pent-4-ynoic acid (1.0 g, 10.20 mmol) in methanol (15mL) was added H₂SO₄ (1.0 g, 10.20 mmol). After stirred at 70° C. for 16h, the reaction was quenched by NaHCO₃ (aq.) (10 mL) and the reactionmixture was extracted with ethyl acetate. The combined organic layerswere dried over anhydrous Na₂SO₄, filtered, and concentrated. Theresidue was purified using silica gel eluting with petroleum ether/ethylacetate (20:1) to give methyl pent-4-ynoate (464 mg) in 46% yield.

To a solution of methyl pent-4-ynoate (191 mg, 1.7 mmol) intetrahydrofuran (20 mL) were added(S)-N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-6-iodo-1,3-dioxoisoindolin-4-yl)acetamide(400 mg, 0.68 mmol), CuI (26 mg, 0.14 mmol), triethylamine (206 mg, 2.04mmol), and Pd(PPh₃)₂Cl₂ (98 mg, 0.14 mmol). The mixture was stirred at70° C. under N₂ atmosphere for 16 h and then concentrated. The residuewas diluted with H₂O and extracted with ethyl acetate. The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered, andconcentrated. The residue was purified using prep-TLC eluting withDCM/MeOH (20:1) to give (S)-methyl5-(7-acetamido-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-5-yl)pent-4-ynoate(212 mg) in 55% yield. MS (ESI) m/z: 571.2 [M+H]⁺.

To a solution of (S)-methyl5-(7-acetamido-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-5-yl)pent-4-ynoate(212 mg, 0.37 mmol) in MeOH (10 mL) was added Pd/C (212 mg). Afterstirred under H₂ atmosphere for 16 h, the mixture was filtered andwashed with dichloromethane. The combined filtrates were concentrated.The residue was purified using prep-TLC eluting with DCM/MeOH (20:1) togive (S)-methyl5-(7-acetamido-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-5-yl)pentanoate(199 mg) in 94% yield. MS (ESI) m/z: 575.2 [M+H]⁺.

To a solution of (S)-methyl5-(7-acetamido-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-5-yl)pentanoate(118 mg, 0.206 mmol) in tetrahydrofuran (10 mL) was added potassiumtrimethylsilanolate (79 mg, 0.618 mmol). The mixture was stirred at 0°C. for 3 h and then concentrated to afford(S)-5-(7-acetamido-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-5-yl)pentanoicacid. MS (ESI) m/z: 561.2 [M+H]⁺.

To a solution of tert-butyl4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidine-1-carboxylate(89 mg, 0.197 mmol) in dichloromethane (8 mL) was added HCl-ethylacetate (2 mL). The mixture was stirred for 1 h and then concentrated togive3-(1-oxo-4-(piperidin-4-ylethynyl)isoindolin-2-yl)piperidine-2,6-dioneHCl salt (75 mg), which was dissolved in N,N-dimethylformamide (1 mL).N,N-Diisopropylethylamine (76 mg, 0.591 mmol) was then added, followedby addition of a solution of(S)-5-(7-acetamido-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-5-yl)pentanoicacid (solution, 0.206 mmol), HOBt (40 mg, 0.296 mmol), and EDCI.HCl (57mg, 0.296 mmol). After stirred overnight, the mixture was diluted withH₂O and extracted with ethyl acetate. The combined organic layers weredried over anhydrous Na₂SO₄, filtered, and concentrated. The residue waspurified using prep-TLC eluting with dichloromethane/methanol (10:1) andfurther purified using prep-HPLC to giveN-(6-(5-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidin-1-yl)-5-oxopentyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamideB16 (6.6 mg) in 4% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 11.00 (s, 1H),9.66 (s, 1H), 8.29 (s, 1H), 7.73 (d, J=7.2 Hz, 1H), 7.66 (d, J=7.6 Hz,1H), 7.54 (d, J=7.6 Hz, 1H), 7.45 (s, 1H), 7.07 (s, 1H), 6.97-6.93 (m,2H), 5.77 (dd, J=4.4, 10.4 Hz, 1H), 5.13 (dd, J=4.4, 12.8 Hz, 1H),4.49-4.31 (m, 4H), 4.15-4.11 (m, 1H), 4.02 (q, J=7.2 Hz, 2H), 3.89-3.84(m, 2H), 3.74 (s, 3H), 3.72-3.57 (m, 2H), 3.22-3.17 (m, 1H), 3.02 (s,3H), 2.97-2.90 (m, 1H), 2.75 (t, J=6.8 Hz, 2H), 2.63-2.59 (m, 2H),2.36-2.33 (m, 2H), 2.18 (s, 3H), 2.04-1.98 (m, 2H), 1.89-1.81 (m, 2H),1.64-1.59 (m, 2H), 1.56-1.49 (m, 2H), 1.33 (t, J=7.2 Hz, 2H); MS (ESI)m/z: 894.3[M+H]⁺.

Example 7 Synthesis ofN-(3,5-Dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((5-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidin-1-yl)-5-oxopentyl)oxy)benzamideB18

A solution of3-(benzyloxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-benzamide(110 mg, 0.271 mmol) in trifluoroacetic acid (6 mL) was stirred at 80°C. for 1 h and then concentrated to giveN-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-hydroxybenzamide(crude). MS (ESI) m/z: 349.0 [M+H]⁺.

To a solution ofN-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-hydroxybenzamide (94mg, 0.270 mmol) in acetonitrile (5 mL) were added potassium carbonate(112 mg, 0.810 mmol) and methyl 5-bromopentanoate (47 mg, 0.243 mmol).After heated at 80° C. overnight, the mixture was diluted with water andextracted with ethyl acetate. The combined organic layers were driedover anhydrous Na₂SO₄, filtered, and concentrated. The residue waspurified using prep-TLC eluting with petroleum ether/ethyl acetate (3:1)to give methyl5-(5-((3,5-dichloropyridin-4-yl)carbamoyl)-2-(difluoromethoxy)phenoxy)pentanoate(75 mg) in 60% yield. MS (ESI) m/z: 463.1 [M+H]⁺.

To a solution of methyl5-(5-((3,5-dichloropyridin-4-yl)carbamoyl)-2-(difluoromethoxy)phenoxy)pentanoate(75 mg, 0.162 mmol) in methanol (4 mL), tetrahydrofuran (2 mL), andwater (1 mL) was added lithium hydroxide (14 mg, 0.325 mmol). Afterstirred for 12 h, the mixture was neutralized to pH 6 with 1N HCl andthen extracted with ethyl acetate. The combined organic layers wereconcentrated to give5-(5-((3,5-dichloropyridin-4-yl)carbamoyl)-2-(difluoromethoxy)phenoxy)pentanoicacid (72 mg) in 99% yield. MS (ESI) m/z: 449.2 [M+H]⁺.

To a solution of5-(5-((3,5-dichloropyridin-4-yl)carbamoyl)-2-(difluoromethoxy)-phenoxy)pentanoicacid (72 mg, 0.162 mmol) in N,N-dimethylformamide (5 mL) were added HATU(93 mg, 0.243 mmol),3-(1-oxo-4-(piperidin-4-ylethynyl)isoindolin-2-yl)piperidine-2,6-dione(57 mg, 0.62 mmol), and ethyldiisopropylamine (63 mg, 0.486 mmol). Themixture was stirred overnight and then concentrated. The residue waspurified using prep-HPLC to giveN-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((5-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidin-1-yl)-5-oxopentyl)oxy)benzamideB18 (36.9 mg) in 29% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 10.98 (s, 1H),10.63 (s, 1H), 8.74 (s, 2H), 7.72-7.70 (m, 2H), 7.66-7.63 (m, 2H), 7.53(t, J=7.6 Hz, 1H), 7.38-7.01 (m, 2H), 5.12 (dd, J=5.2, 13.6 Hz, 1H),4.47-4.29 (m, 2H), 4.15 (t, J=6.4, 2H), 3.90-3.87 (m, 1H), 3.73-3.69 (m,1H), 3.29 (s, 2H), 3.22-3.16 (m, 1H), 2.99-2.86 (m, 2H), 2.66-2.57 (m,1H), 2.45-2.38 (m, 3H), 2.07-1.95 (m, 2H), 1.71-1.66 (m, 2H), 1.23 (s,4H); MS (ESI) m/z: 782.2 [M+H]⁺.

Example 8 Synthesis of7-((4-((5-((S)-2,6-Dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)benzyl)amino)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)heptanamideB44

To a stirred solution of 7-(((benzyloxy)carbonyl)amino)heptanoic acid(500 mg, 1.79 mmol) in toluene (10 mL) was added thionyl chloride (1.1g, 9.24 mmol). The mixture was stirred at 100° C. for 2 h and thenconcentrated to give benzyl (7-chloro-7-oxoheptyl)carbamate (crude).

To a stirred solution of benzyl (7-chloro-7-oxoheptyl)carbamate (1.79mmol) in tetrahydrofuran (10 mL) was added(S)-4-amino-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)isoindoline-1,3-dione(375 mg, 0.9 mmol). The mixture was stirred for 3 days and thenconcentrated. The residue was purified using silica gel eluting withethyl acetate in petroleum ether from 20% to 50% to give (S)-benzyl(7-((2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)amino)-7-oxoheptyl)carbamate(565 mg) in 93% yield. MS (ESI) m/z: 680.2 [M+H]⁺.

To a stirred solution of (S)-benzyl(7-((2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)amino)-7-oxoheptyl)carbamate(200 mg, 0.29 mmol) in methanol (5 mL) was added 10% Pd/C (200 mg).After stirred at room temperature overnight under hydrogen, the mixturewas filtered and the filtrate was concentrated to give(S)-7-amino-N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)heptanamide(135 mg) in 84% yield. MS (ESI) m/z: 546.2 [M+H]⁺.

To a stirred solution of(S)-7-amino-N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)heptanamide(135 mg, 0.25 mmol) and(S)-4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)benzaldehyde(95 mg, 0.25 mmol) in dichloromethane (4 mL) and methanol (1 mL) wereadded sodium cyanoborohydride (32 mg, 0.5 mmol) and acetic acid (2drops). The mixture was stirred overnight then concentrated. The residuewas purified using prep-TLC (dichloromethane/methanol (10:1) and furtherpurified using prep-HPLC to give7-((4-((5-((S)-2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)benzyl)amino)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)heptanamideB44 (8.0 mg). ¹H NMR (400 MHz, DMSO-d₆) δ 10.99 (s, 1H), 9.66 (s, 1H),8.66 (brs, 2H), 8.46 (d, J=8.4 Hz, 1H), 8.03 (s, 1H), 7.79 (t, J=8.0 Hz,1H), 7.57 (d, J=7.2 Hz, 1H), 7.42 (d, J=8.8 Hz, 2H), 7.12-7.07 (m, 3H),7.00-6.92 (m, 2H), 5.77 (dd, J=4.0, 10.4 Hz, 1H), 5.34 (s, 2H), 5.02(dd, J=4.8, 13.2 Hz, 1H), 4.38-4.30 (m, 2H), 4.24-4.12 (m, 2H), 4.07 (t,J=4.8 Hz, 2H), 4.01 (q, J=6.4 Hz, 2H), 3.73 (s, 3H), 3.01 (s, 3H),2.97-2.85 (m, 3H), 2.67-2.53 (m, 1H), 2.49-2.46 (m, 2H), 2.38-2.28 (m,1H), 2.02-1.97 (m, 1H), 1.66-1.58 (m, 4H), 1.38-1.30 (m, 7H); MS (ESI)m/z: 914.2 [M+H]⁺.

Example 9 Synthesis of14-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)-3,6,9,12-tetraoxatetradecan-1-amideB48

To a stirred solution of2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecan-19-oic acid (300mg, 0.85 mmol) in dichloromethane (10 mL) were added oxalyl chloride(130 mg, 1.02 mmol) and 1 drop of N,N-dimethylformamide. The mixture wasstirred for 2 h and then concentrated to give tert-butyl(14-chloro-14-oxo-3,6,9,12-tetraoxatetradecyl)carbamate (300 mg, crude).

To a stirred solution of tert-butyl(14-chloro-14-oxo-3,6,9,12-tetraoxatetradecyl)-carbamate (0.85 mmol) intetrahydrofuran (10 mL) was added(S)-4-amino-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)isoindoline-1,3-dione(120 mg, 0.287 mmol). The mixture was stirred overnight and thenconcentrated. The residue was purified using prep-TLC eluting withdichloromethane/methanol (20:1) to give(S)-14-amino-N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)-3,6,9,12-tetraoxatetradecan-1-amide(90 mg) in 48% yield. MS (ESI) m/z: 652.2 [M+H]⁺.

To a stirred solution of(S)-14-amino-N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)-3,6,9,12-tetraoxatetradecan-1-amide(90 mg, 0.14 mmol) and2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (41 mg, 0.15mmol) in 1-methyl-2-pyrrolidinone (3 mL) was added ethyldiisopropylamine(54 mg, 0.42 mmol). The mixture was stirred at 150° C. for 1 h undermicrowave. Water was added and the mixture was extracted withdichloromethane. The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered, and concentrated. Theresidue was purified using prep-HPLC to give14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)-3,6,9,12-tetraoxatetradecan-1-amideB48 (9.8 mg) in 8% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H),10.35 (s, 1H), 8.67 (d, J=8.8 Hz, 1H), 7.81 (t, J=8.0 Hz, 1H), 7.58-7.52(m, 2H), 7.10-7.08 (m, 2H), 7.02-6.91 (m, 3H), 6.56 (t, J=5.2 Hz, 1H),5.78 (dd, J=4.0, 10.4 Hz, 1H), 5.04 (dd, J=5.2, 12.4 Hz, 1H), 4.35-4.12(m, 4H), 4.01 (q, J=7.2 Hz, 2H), 3.76-3.72 (m, 5H), 3.68-3.64 (m, 2H),3.58-3.55 (m, 2H), 3.54-3.52 (m, 2H), 3.49-3.46 (m, 8H), 3.01 (s, 3H),2.88-2.82 (m, 1H), 2.60-2.53 (m, 2H), 2.04-1.99 (m, 1H), 1.31 (t, J=7.2Hz, 3H); MS (ESI) m/z: 908.2 [M+H]⁺.

Example 10 Synthesis of2-(3-(Cyclopentyloxy)-4-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)oxy)phenyl)isoindoline-1,3-dioneB59

To a solution of 1-(benzyloxy)-2-(cyclopentyloxy)-4-nitrobenzene (1.0 g,3.19 mmol) in acetic acid (4 mL) was added hydrogen bromide (2 mL, 33%in AcOH). The mixture was stirred for 3 h and then concentrated to give2-(cyclopentyloxy)-4-nitrophenol (500 mg, crude). MS (ESI) m/z:224.1[M+H]⁺.

To a solution of 2-(cyclopentyloxy)-4-nitrophenol (400 mg, 1.79 mmol) inN,N-dimethylformamide (5 mL) at 80° C. were added7-iodo-N-methoxy-N-methylheptanamide (803 mg, 2.69 mmol) and potassiumcarbonate (494 mg, 3.58 mmol). After stirred at 80° C. overnight, themixture was diluted with H₂O and extracted with ethyl acetate. Thecombined organic layers were dried over anhydrous sodium sulfate,filtered, and concentrated. The residue was purified using silica geleluting with methanol in dichloromethane from 0% to 5% to give7-(2-(cyclopentyloxy)-4-nitrophenoxy)-N-methoxy-N-methylheptanamide (604mg) in 86% yield. MS (ESI) m/z: 395.2[M+H]⁺.

To a solution of7-(2-(cyclopentyloxy)-4-nitrophenoxy)-N-methoxy-N-methylheptanamide (400mg, 1.0 mmol) in tetrahydrofuran (5 mL) at −75° C. under nitrogen wasadded lithium aluminum hydride (1.5 mL, 1 M in tetrahydrofuran)dropwise. After stirred at this temperature for 1 h, the reaction wasquenched with ammonium chloride (5 mL) and the reaction mixture wasextracted with ethyl acetate. The combined organic layers were driedover anhydrous sodium sulfate, filtered, and concentrated to give7-(2-(cyclopentyloxy)-4-nitrophenoxy)heptanal (350 mg, crude). MS (ESI)m/z: 336.2[M+H]⁺.

To a solution of 7-(2-(cyclopentyloxy)-4-nitrophenoxy)heptanal (335 mg,1 mmol, crude) in dichloromethane (5 mL) was added3-(6-fluoro-1-oxo-4-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione(414 mg, crude, 1.2 mmol), followed by addition of sodiumcyanoborohydride (126 mg, 2.0 mmol). The mixture was stirred for 2 h andthen concentrated. The residue was purified using silica gel elutingwith methanol in dichloromethane from 0% to 5% to give3-(4-(1-(7-(2-(cyclopentyloxy)-4-nitrophenoxy)heptyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione(664 mg, crude). MS (ESI) m/z: 665.3[M+H]⁺.

To a solution of3-(4-(1-(7-(2-(cyclopentyloxy)-4-nitrophenoxy)heptyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione(800 mg, crude) in tetrahydrofuran (20 mL) was added Pd/C (300 mg).After stirred under H₂ overnight, the mixture was filtered and thefiltrate was concentrated to give3-(4-(1-(7-(4-amino-2-(cyclopentyloxy)phenoxy)heptyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione(700 mg) in 73% yield. MS (ESI) m/z: 635.3[M+H]⁺.

To a stirred solution of3-(4-(1-(7-(4-amino-2-(cyclopentyloxy)phenoxy)heptyl)-piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione(300 mg, 0.47 mmol) in acetic acid (15 mL) was addedisobenzofuran-1,3-dione (84.2 mg, 0.57 mmol). The mixture was stirred at90° C. for 4 h. Water was then added and the mixture was extracted withethyl acetate. The combined organic layers were washed with brine, driedover anhydrous sodium sulfate, filtered, and concentrated. The residuewas purified using prep-HPLC to give2-(3-(cyclopentyloxy)-4-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)oxy)phenyl)-isoindoline-1,3-dioneB59 (11.3 mg) in 3% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H),9.39 (s, 1H), 7.96-7.89 (m, 4H), 7.43 (dd, J=2.0, 7.2 Hz, 1H), 7.31 (dd,J=1.6, 10.8 Hz, 1H), 7.14-7.01 (m, 2H), 6.93 (dd, J=2.0, 8.8 Hz, 1H),5.16 (dd, J=4.8, 13.2 Hz, 1H), 4.85 (s, 1H), 4.56-4.36 (m, 2H), 4.02 (t,J=6.0 Hz, 2H), 3.61-3.51 (m, 3H), 3.02-2.89 (m, 6H), 2.66-2.61 (m, 1H),2.40-2.29 (m, 1H), 2.07-1.85 (m, 6H), 1.77-1.71 (m, 6H), 1.60-1.55 (m,2H), 1.48-1.37 (m, 6H); MS (ESI) m/z: 765.4 [M+H]⁺.

Example 11 Synthesis ofN-(3,5-Dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperidin-1-yl)heptyl)oxy)benzamideB61

To a solution ofN-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-(methoxy(methyl)amino)-7-oxoheptyl)oxy)benzamide(80 mg, 0.154 mmol) in tetrahydrofuran (5 mL) at −78° C. under nitrogenwas added lithium aluminum hydride (0.23 mL, 1 M in tetrahydrofuran)dropwise. After stirred at this temperature for 1 h, the reaction wasquenched with ammonium chloride (5 mL) and the reaction mixture wasextracted with ethyl acetate. The combined organic layers were driedover anhydrous sodium sulfate, filtered, and concentrated to giveN-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-oxoheptyl)oxy)benzamide(71 mg, crude). MS (ESI) m/z: 461.1[M+H]⁺.

To a solution of tert-butyl4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperidine-1-carboxylate(60 mg, 0.135 mmol) in dichloromethane (3 mL) was added trifluoroaceticacid (1 mL). The mixture was stirred for 1 h and then concentrated. Theresidue was co-evaporated with toluene to give3-(6-fluoro-1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione(47 mg, crude). MS (ESI) m/z: 346.1 [M+H]⁺.

To a solution of3-(6-fluoro-1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione(47 mg, 0.135 mmol) in dichloromethane (4 mL) and methanol (1 mL) at 0°C. was added N,N-diisopropylethylamine (35 mg, 0.27 mmol), followed byaddition ofN-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-oxoheptyl)oxy)benzamide(71 mg, crude, 0.154 mmol), NaBH₃CN (17 mg, 0.27 mmol), and acetic acid(1 drop). The mixture was stirred at room temperature for 8 h and thenconcentrated. The residue was purified using silica gel eluting withmethanol in dichloromethane from 0% to 10% to giveN-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperidin-1-yl)heptyl)oxy)benzamideB61 (28.0 mg) in 26.4% yield. ¹HNMR (DMSO-d₆, 400 MHz) δ 10.99 (s, 1H),10.66 (s, 1H), 8.76 (s, 2H), 7.72 (d, J=2.0 Hz, 1H), 7.65 (dd, J=1.6,8.0 Hz, 1H), 7.61 (d, J=6.4 Hz, 1H), 7.46 (d, J=9.2 Hz, 1H), 7.38-7.01(m, 2H), 5.10 (dd, J=4.8, 12.8 Hz, 1H), 4.32-4.26 (m, 2H), 4.13 (t,J=6.4 Hz, 2H), 2.99-2.96 (m, 2H), 2.94-2.83 (m, 2H), 2.67-2.58 (m, 1H),2.43-2.36 (m, 1H), 2.36-2.28 (m, 3H), 2.03-1.98 (m, 3H), 1.79-1.72 (m,6H), 1.48-1.44 (m, 4H), 1.38-1.29 (m, 4H); MS (ESI) m/z: 790.3 [M+H]⁺.

Example 12 Synthesis ofN¹-(2-((S)-1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)-N¹⁰-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)decanediamideB63

To a stirred solution of 10-(tert-butoxy)-10-oxodecanoic acid (370 mg,1.43 mmol) in dichloromethane (10 mL) were added oxalyl chloride (182mg, 1.43 mmol) and 2 drops of N,N-dimethylformamide. The mixture wasstirred at 0° C. for 2 h and then concentrated to give tert-butyl10-chloro-10-oxodecanoate (350 mg, crude).

To a stirred solution of tert-butyl 10-chloro-10-oxodecanoate (1.43mmol) in tetrahydrofuran (10 mL) was added(S)-4-amino-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)isoindoline-1,3-dione(200 mg, 0.47 mmol). The mixture was stirred for 2 days and thenconcentrated. The residue was purified using silica gel eluting withethyl acetate in petroleum ether from 20% to 50% to give (S)-tert-butyl10-((2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)amino)-10-oxodecanoate(207 mg) in 43% yield. MS (ESI) m/z: 659.3 [M+H]⁺.

To a stirred solution of (S)-tert-butyl10-((2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)amino)-10-oxodecanoate(100 mg, 0.15 mmol) in dichloromethane (4 mL) was added trifluoroaceticacid (1 mL). The mixture was stirred for 1 h and then concentrated togive(S)-10-((2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)amino)-10-oxodecanoicacid. MS (ESI) m/z: 603.2 [M+H]⁺.

To a stirred solution of(S)-10-((2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)amino)-10-oxodecanoicacid (91 mg, 0.15 mmol) in N,N-dimethylformamide (3 mL) was added(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(64.5 mg, 0.35 mmol), followed by addition of ethyldiisopropylamine (59mg, 0.45 mmol), 1-hydroxybenzotriazole (31 mg, 0.22 mmol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (44 mg, 0.22mmol). The mixture was stirred overnight and then concentrated. Theresidue was purified using prep-HPLC to giveN¹-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)-N¹⁰-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)-carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)decanediamideB63 (31.8 mg) in 20% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 9.66 (s, 1H),8.98 (s, 1H), 8.56 (t, J=6.0 Hz, 1H), 8.46 (d, J=8.4 Hz, 1H), 7.85-7.76(m, 2H), 7.56 (d, J=7.2 Hz, 1H), 7.43-7.37 (m, 4H), 7.08-7.07 (m, 1H),6.99-6.92 (m, 2H), 5.77 (dd, J=4.0, 10.4 Hz, 1H), 5.11 (d, J=3.6 Hz,1H), 4.54 (d, J=9.6 Hz, 1H), 4.46-4.12 (m, 6H), 4.02 (q, J=6.8 Hz, 2H),3.73 (s, 3H), 3.68-3.62 (m, 2H), 3.01 (s, 3H), 2.47-2.44 (m, 5H),2.29-2.22 (m, 1H), 2.13-2.10 (m, 1H), 2.02-2.00 (m, 1H), 1.93-1.86 (m,1H), 1.62-1.44 (m, 4H), 1.33-1.25 (m, 11H), 0.92 (s, 9H); MS (ESI) m/z:1015.4 [M+H]⁺.

Example 13 Synthesis of5-(3-((7-(4-(2-(2,6-Dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)oxy)-4-methoxyphenyl)-4H-thieno[2,3-c]pyrrole-4,6(5H)-dioneB65

To a solution of methyl 2-methoxy-5-nitrophenol (400 mg, 2.37 mmol) inN,N-dimethylformaine (5 mL) were added 7-iodo-N-methoxyheptanamide (778mg, 2.60 mmol) and K₂CO₃ (654 mg, 4.74 mmol). After stirred at 60° C.for 4 h, the mixture was diluted with H₂O and extracted with ethylacetate. The combined organic layers were dried over anhydrous Na₂SO₄,filtered, and concentrated. The residue was purified using silica geleluting with ethyl acetate in petroleum ether from 0% to 50% to giveN-methoxy-7-(2-methoxy-5-nitrophenoxy)-N-methylheptanamide (800 mg) in72.1% yield. MS (ESI) m/z: 341.3[M+H]⁺.

To a solution ofN-methoxy-7-(2-methoxy-5-nitrophenoxy)-N-methylheptanamide (190 mg, 0.56mmol) in tetrahydrofuran (4 mL) at −70° C. under nitrogen was addedlithium aluminum hydride (0.8 mL, 1 M in tetrahydrofuran) dropwise.After stirred at this temperature for 1 h, the reaction was quenchedwith ammonium chloride (5 mL) and the reaction mixture was extractedwith ethyl acetate. The combined organic layers were dried overanhydrous sodium sulfate, filtered, and concentrated to give7-(2-methoxy-5-nitrophenoxy)heptanal (157 mg, crude). MS (ESI) m/z:282.3 [M+H]⁺.

To a solution of3-(6-fluoro-1-oxo-4-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione(96 mg, crude, 0.28 mmol) in dichloromethane (4 mL) and methanol (1 mL)was added N,N-diisopropylethylamine (35 mg, 0.28 mmol) at 0° C.,followed by addition of 7-(2-methoxy-5-nitrophenoxy)heptanal (82 mg,crude, 0.28 mmol), NaBH₃CN (35 mg, 0.56 mmol), and acetic acid (1 drop).The mixture was stirred at room temperature overnight and thenconcentrated. The residue was purified using silica gel eluting withmethanol in dichloromethane from 0% to 10% to give3-(6-fluoro-4-(1-(7-(2-methoxy-5-nitrophenoxy)heptyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(101 mg) in 65% yield. MS (ESI) m/z: 611.6 [M+H]⁺.

To a solution of3-(6-fluoro-4-(1-(7-(2-methoxy-5-nitrophenoxy)heptyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(101 mg, 0.17 mmol) in acetic acid (5 mL) was added Fe powder (10 mg,0.50 mmol). After stirred for 1 h, the mixture was filtered and thefiltrate was concentrated to give3-(4-(1-(7-(5-amino-2-methoxyphenoxy)heptyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione(41 mg, crude). MS (ESI) m/z: 581.6 [M+H]⁺.

To a solution of3-(4-(1-(7-(5-amino-2-methoxyphenoxy)heptyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione(41 mg, 0.068 mmol) in acetic acid (3 mL) was addedthieno[2,3-c]furan-4,6-dione (10 mg, 0.068 mmol). The mixture wasstirred at 90° C. overnight and then concentrated. Carbonyl diimidazole((44 mg, 0.272 mmol) and tetrahydrofuran (4 mL) were added. The mixturewas stirred at 75° C. for 2 h and then concentrated. The residue waspurified using prep-HPLC to give5-(3-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)oxy)-4-methoxyphenyl)-4H-thieno[2,3-c]pyrrole-4,6(5H)-dioneB65. ¹H NMR (400 MHz, DMSO-d₆) δ 11.00 (s, 1H), 8.29 (d, J=4.8 Hz, 1H),7.55 (d, J=4.8 Hz, 1H), 7.40 (dd, J=2.4, 10.8 Hz, 1H), 7.34 (dd, J=2.0,7.2 Hz, 1H), 7.06-7.04 (m, 2H), 6.91 (dd, J=2.0 Hz, 8.4 Hz, 1H), 5.13(dd, J=5.2, 13.2 Hz, 1H), 4.52-4.31 (m, 2H), 3.92 (t, J=6.4 Hz, 2H),3.80 (s, 3H), 2.97-2.95 (m, 2H), 2.62-2.57 (m, 2H), 2.45-2.41 (m, 1H),2.28 (t, J=7.2 Hz, 2H), 2.03-1.95 (m, 4H), 1.75-1.68 (m, 6H), 1.47-1.30(m, 8H); MS (ESI) m/z: 717.3 [M+H]⁺.

Example 14 Synthesis of(2S,4R)-1-((S)-2-(9-(5-((3,5-Dichloropyridin-4-yl)carbamoyl)-2-(difluoromethoxy)phenoxy)nonanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamideB68

To a solution of 4-(difluoromethoxy)-3-hydroxybenzaldehyde (150 mg, 0.79mmol) in acetonitrile (10 mL) were added methyl 9-bromononanoate (260mg, 1.02 mmol) and potassium carbonate (330 mg, 2.3 mmol). After stirredat 80° C. overnight, the reaction was quenched with ammonium chloride(10 mL) and the reaction mixture was extracted with ethyl acetate. Thecombined organic layers were dried over anhydrous sodium sulfate,filtered, and concentrated to give methyl9-(2-(difluoromethoxy)-5-formylphenoxy)nonanoate (217 mg, crude). MS(ESI) m/z: 359.1[M+H]⁺.

To a solution of methyl 9-(2-(difluoromethoxy)-5-formylphenoxy)nonanoate(200 mg, 0.55 mmol) in acetic acid (10 mL) and water (10 mL) at 0° C.were added sulfamic acid (150 mg, 1.66 mmol) and sodium hypochlorite(162 mg, 1.67 mmol). After stirred at 0° C. for 30 min, the mixture wasdiluted with water and extracted with ethyl acetate. The combinedorganic layers were dried over anhydrous sodium sulfate, filtered, andconcentrated to give4-(difluoromethoxy)-3-((9-methoxy-9-oxononyl)oxy)benzoic acid (210 mg)in 89% yield. MS (ESI) m/z: 375.2 [M+H]⁺.

To a solution of4-(difluoromethoxy)-3-((9-methoxy-9-oxononyl)oxy)benzoic acid (100 mg,0.27 mmol) in dichloromethane (10 mL) at 0° C. were added oxalylchloride (51 mg, 0.41 mmol) and N,N-dimethylformamide (1drop). Themixture was stirred at 0° C. for 3 h and then concentrated to givemethyl 9-(5-(chlorocarbonyl)-2-(difluoromethoxy)phenoxy)nonanoate(crude).

To a solution of 3,5-dichloropyridin-4-amine (65 mg, 0.41 mmol) inN,N-dimethylformamide (5 mL) at 0° C. was added NaH (21 mg, 0.54 mmol).After the mixture was stirred at this temperature for 30 min, a solutionof methyl 9-(5-(chlorocarbonyl)-2-(difluoromethoxy)phenoxy)nonanoate(crude) in N,N-dimethylformamide (5 mL) was added. The reaction wasstirred at 0° C. overnight and then quenched with water. The reactionmixture was extracted with ethyl acetate. The combined organic layerswere dried over anhydrous sodium sulfate, filtered, and concentrated togive methyl9-(5-((3,5-dichloropyridin-4-yl)carbamoyl)-2-(difluoromethoxy)phenoxy)nonanoate(50 mg, crude). MS (ESI) m/z: 519.2 [M+H]⁺.

To a solution of methyl9-(5-((3,5-dichloropyridin-4-yl)carbamoyl)-2-(difluoromethoxy)phenoxy)nonanoate(50 mg, 0.096 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was addedlithium hydroxide monohydrate (7.8 mg, 0.19 mmol). After stirred for 8h, the mixture was acidified to pH 5 with 2N HCl and extracted withethyl acetate. The combined organic layers were dried over anhydroussodium sulfate, filtered, and concentrated to give9-(5-((3,5-dichloropyridin-4-yl)carbamoyl)-2-(difluoromethoxy)phenoxy)nonanoicacid (37 mg, crude). MS (ESI) m/z: 504.1[M+H]⁺.

To a solution of9-(5-((3,5-dichloropyridin-4-yl)carbamoyl)-2-(difluoromethoxy)-phenoxy)nonanoicacid (37 mg, 0.073 mmol) in N,N-dimethylformamide (10 mL) at roomtemperature were added(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(34.2 mg, 0.073 mmol), N,N-diisopropylethylamine (28.3 mg, 0.219 mmol),HOBt (19.7 mg, 0.146 mmol), and EDCI.HCl (28.1 mg, 0.146 mmol). Afterstirred overnight, the mixture was diluted with H₂O and extracted withethyl acetate. The combined organic layers were dried over anhydroussodium sulfate, filtered, and concentrated. The residue was purifiedusing prep-HPLC to give(2S,4R)-1-((S)-2-(9-(5-((3,5-dichloropyridin-4-yl)carbamoyl)-2-(difluoromethoxy)phenoxy)nonanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamideB68 (12 mg). ¹H NMR (400 MHz, DMSO-d₆) δ 10.66 (s, 1H), 8.98 (s, 1H),8.76 (s 2H), 8.56 (t, J=5.2 Hz, 1H), 7.84 (d, J=9.2 Hz, 1H), 7.71 (s,1H), 7.65 (d, J=7.6 Hz, 1H), 7.42-7.36 (m, 5H), 7.18 (t, J=74.0 Hz, 1H),5.13 (d, J=3.6 Hz, 1H), 4.53 (d, J=9.6 Hz, 1H), 4.46-4.40 (m, 2H), 4.34(s, 1H), 4.24-4.19 (m, 1H), 4.11 (t, J=6.0 Hz, 2H), 3.68-3.62 (m, 2H),2.44 (s, 3H), 2.29-2.22 (m, 1H), 2.14-2.08 (m, 1H), 2.05-1.99 (m, 1H),1.92-1.86 (m, 1H), 1.78-1.73 (m, 2H), 1.53-1.43 (m, 4H), 1.29-1.23 (m,6H), 0.92 (s, 9H); MS (ESI) m/z: 917.3[M+H]⁺.

Example 15 Synthesis ofN-(6-(3-(4-(2-(2,6-Dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)propyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamideB69

To a solution of(S)-N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-6-iodo-1,3-dioxoisoindolin-4-yl)acetamide(100 mg, 0.17 mmol) and3-(6-fluoro-1-oxo-4-(1-(prop-2-yn-1-yl)piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione(130 mg, 0.34 mmol) in 5 mL of THF were added Pd(PPh₃)₂Cl₂ (24 mg, 0.034mmol), CuI (6.5 mg, 0.034 mmol), and triethylamine (52 mg, 0.51 mmol)under N₂. After stirred at 70° C. for 3 h, the mixture was concentratedand purified using prep-TLC eluting with ethyl acetate to affordN-(6-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide(95 mg) in 66% yield. MS (ESI) m/z: 842.2 [M+H]⁺.

To a mixture ofN-(6-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)prop-1-yn-1-yl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide(95 mg, 0.11 mmol) in 2 mL of THF was added Pd/C (10 mg). After stirredunder H₂ for 48 h, the mixture was filtered and washed with ethylacetate. The filtrate was concentrated and the residue purified usingprep-HPLC to affordN-(6-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)propyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamideB69 (31 mg) in 32% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 11.01 (s, 1H),9.64 (s, 1H), 8.28 (s, 1H), 7.47 (s, 1H), 7.40 (dd, J=2.0, 11.2 Hz, 1H),7.34 (dd, J=2.0, 7.2 Hz, 1H), 7.06 (s, 1H), 6.98-6.90 (m, 2H), 5.75 (dd,J=4.4, 10.4 Hz, 1H), 5.13 (dd, J=4.8, 13.2 Hz, 1H), 4.52-4.33 (m, 3H),4.15-4.09 (m, 1H), 4.01(q, J=6.8 Hz, 2H), 3.73 (s, 3H), 3.01 (s, 3H),2.96-2.89 (m, 3H), 2.76-2.65 (m, 2H), 2.64-2.54 (m, 2H), 2.46-2.39 (m,1H), 2.29-2.21 (m, 2H), 2.18 (s, 3H), 2.06-1.86 (m, 3H), 1.78-1.64 (m,4H), 1.63-1.52 (m, 2H), 1.32 (t, J=6.8 Hz, 3H)); MS (ESI) m/z: 846.1[M+H]⁺.

Example 16 Synthesis of12-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)dodecanamideB71

To a stirred solution of 12-aminododecanoic acid (1 g, 4.65 mmol) in 2Nsodium hydroxide (15 mL) at 0° C. was added benzyl chloroformate (951mg, 5.58 mmol) in 2N sodium hydroxide (15 mL). After stirred at 0° C.for 2 h, the mixture was diluted with H₂O and extracted with methyltert-butyl ether. The aqueous layer was acidified to pH 3-4 with 1Nhydrochloric acid and extracted with methyl tert-butyl ether. Theorganic layers were combined, dried over anhydrous sodium sulfate,filtered, and concentrated to give12-(((benzyloxy)carbonyl)-amino)dodecanoic acid (700 mg) in 43% yield.MS (ESI) m/z: 350.2 [M+H]⁺.

To a stirred solution of 12-(((benzyloxy)carbonyl)amino)dodecanoic acid(700 mg, 2 mmol) in toluene (7 mL) was added thionyl chloride (1.19 g,10 mmol). The mixture was stirred at 100° C. for 2 h and thenconcentrated to give benzyl (12-chloro-12-oxododecyl)carbamate (1.2 g,crude).

To a stirred solution of benzyl (12-chloro-12-oxododecyl)carbamate (1.2g, 2 mmol) in tetrahydrofuran (4 mL) were added(S)-4-amino-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)isoindoline-1,3-dione(418 mg, 1 mmol) and triethylamine (4 mL). The mixture was stirred for 3days and then concentrated. The residue was purified using silica geleluting with ethyl acetate in petroleum ether from 0 to 50% to give(S)-benzyl(12-((2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)amino)-12-oxododecyl)-carbamate(441 mg) in 59% yield. MS (ESI) m/z: 750.2 [M+H]⁺.

To a stirred solution of (S)-benzyl(12-((2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)amino)-12-oxododecyl)carbamate(441 mg, 0.59 mmol) in methanol (9 mL) and dichloromethane (1 mL) wasadded Pd/C (200 mg). After stirred overnight under hydrogen, the mixturewas filtered and the filtrate was concentrated to give(S)-12-amino-N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)dodecanamide(350 mg) in 96% yield. MS (ESI) m/z: 616.2 [M+H]⁺.

To a stirred solution of(S)-12-amino-N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)dodecanamide(180 mg, 0.29 mmol) in N,N-dimethylformamide (3 mL) were added2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (96 mg, 0.35mmol) and N,N-diisopropylethylamine (112 mg, 0.87 mmol). After stirredat 150° C. for 1 h under microwave, the mixture was diluted with waterand extracted with ethyl acetate. The combined organic layers were driedover anhydrous sodium sulfate, filtered, and concentrated. The residuewas purified using prep-TLC eluting with petroleum ether/ethyl acetate(1:2) and further purified using prep-HPLC to give12-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)dodecanamideB71 (27.3 mg). ¹H NMR (400 MHz, DMSO-d₆) δ 11.11 (s, 1H), 9.66 (s, 1H),8.48 (d, J=8.4 Hz, 1H), 7.79 (t, J=7.6 Hz, 1H), 7.59-7.55 (m, 2H),7.10-7.06 (m, 2H), 7.03-6.99 (m, 2H), 6.94 (d, J=8.0 Hz, 1H), 6.51 (t,J=5.2 Hz, 1H), 5.80 (dd, J=3.6, 10.0 Hz, 1H), 5.06 (dd, J=5.2, 12.8 Hz,1H), 4.39-4.34 (m, 1H), 4.16 (dd, J=3.6, 14.4 Hz, 1H), 4.01 (q, J=6.8Hz, 2H), 3.74 (s, 3H), 3.29-3.26 (m, 2H), 3.03 (s, 3H), 2.93-2.86 (m,1H), 2.63-2.55 (m, 2H), 2.48-2.45 (m, 2H), 2.08-2.02 (m, 1H), 1.63-1.54(m, 4H), 1.35-1.25 (m, 17H); MS (ESI) m/z: 872.4 [M+H]⁺.

Example 17 Synthesis of9-(4-(2-(2,6-Dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperidin-1-yl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)nonanamideB75

To a solution of 9-methoxy-9-oxononanoic acid (800 mg, 3.95 mmol) indichloromethane (15 mL) was added oxalyl chloride (753 mg, 5.93 mmol),followed by addition DMF (1 drop). The mixture was stirred for 2 h andthen concentrated to give methyl 9-chloro-9-oxononanoate (869 mg,crude).

To a solution of(S)-4-amino-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethyl)isoindoline-1,3-dione(823 mg, 1.97 mmol) in pyridine (10 mL) at 0° C. was added methyl9-chloro-9-oxononanoate (869 mg, 3.95 mmol, crude). The mixture wasstirred at room temperature overnight and then concentrated. The residuewas purified using silica gel eluting with ethyl acetate in petroleumether from 10% to 50% to give (S)-methyl9-((2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)amino)-9-oxononanoate(659 mg) in 56% yield. MS (ESI) m/z: 603.2 [M+H]⁺.

To a solution of (S)-methyl9-((2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethyl)-1,3-dioxoisoindolin-4-yl)amino)-9-oxononanoate(659 mg, 1.09 mmol) in toluene (15 mL) at −70° C. under N₂ was addedDIBAL-H (2.19 mL, 1 M in THF). After stirred at this temperature for 30min, the reaction was quenched with sat. NH₄Cl (5 mL) and the reactionmixture was extracted with ethyl acetate. The combined organic layerswere dried over anhydrous Na₂SO₄, filtered, and concentrated to give(S)-N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)-9-oxononanamide(218 mg) in 35% yield. MS (ESI) m/z: 573.2[M+H]⁺.

To a solution of(S)-N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)-9-oxononanamide(218 mg, 0.13 mmol) in dichloromethane/methanol (8 mL/2 mL) were added3-(6-fluoro-1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione(62 mg, 0.18 mmol) and N,N-diisopropylethylamine (23 mg, 0.18 mmol),followed by addition of NaBH₃CN (16 mg, 0.266 mmol). The mixture wasstirred overnight and then concentrated. The residue was purified usingsilica gel eluting with methanol in dichloromethane from 0% to 10% andfurther purified using prep-HPLC to give9-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperidin-1-yl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)nonanamideB75 (43.4 mg) in 36% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 10.99 (s, 1H),9.67 (s, 1H), 8.46 (d, J=8.4 Hz, 1H), 7.78 (t, J=8.0 Hz, 1H), 7.59 (d,J=5.6 Hz, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.08 (d,J=1.6 Hz, 1H), 6.99-6.92 (m, 2H), 5.77 (dd, J=4.4, 10.4 Hz, 1H), 5.11(dd, J=4.8, 13.2 Hz, 1H), 4.43-4.26 (m, 3H), 4.15 (dd, J=4.4, 14.4 Hz,1H), 4.02 (q, J=6.8 Hz, 2H), 3.73 (s, 3H), 3.01 (s, 3H), 2.97-2.84 (m,4H), 2.61-2.57 (m, 1H), 2.47-2.45 (m, 2H), 2.41-2.36 (m, 1H), 2.27 (t,J=6.8 Hz, 2H), 2.01-1.90 (m, 3H), 1.71-1.61 (m, 6H), 1.44-1.41 (m, 2H),1.34-1.30 (m, 12H); MS (ESI) m/z: 902.4 [M+H]⁺.

Example 18 Synthesis of(2S,4R)-1-((S)-2-(11-(5-((3,5-Dichloropyridin-4-yl)carbamoyl)-2-(difluoromethoxy)phenoxy)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamideB76

A solution of3-(benzyloxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-benzamide(120 mg, 0.274 mmol) in trifluoroacetic acid (6 mL) was heated at 80° C.for 1 h and then concentrated to giveN-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-hydroxybenzamide(crude). MS (ESI) m/z: 349.0 [M+H]⁺.

To a solution ofN-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-hydroxybenzamide (95mg, 0.273 mmol) in acetonitrile (6 mL) were added potassium carbonate(113 mg, 0.819 mmol) and tert-butyl 11-bromoundecanoate (96 mg, 0.30mmol). After heated at 80° C. overnight, the mixture was diluted withwater and extracted with ethyl acetate. The combined organic layers wereconcentrated. The residue was purified using silica gel eluting withethyl acetate in petroleum from 0% to 20% to give tert-butyl11-(5-((3,5-dichloropyridin-4-yl)carbamoyl)-2-(difluoromethoxy)phenoxy)undecanoate(86 mg) in 54% yield. MS (ESI) m/z: 533.2 [M−56+H]⁺.

To a solution of tert-butyl11-(5-((3,5-dichloropyridin-4-yl)carbamoyl)-2-(difluoromethoxy)phenoxy)undecanoate(86 mg, 0.146 mmol) in dichloromethane (6 mL) was trifluoroacetic acid(2 mL). The mixture was stirred for 12 h and then concentrated to give11-(5-((3,5-dichloropyridin-4-yl)carbamoyl)-2-(difluoromethoxy)phenoxy)undecanoicacid (70 mg, crude). MS (ESI) m/z: 533.2 [M+H]⁺.

To a solution of11-(5-((3,5-dichloropyridin-4-yl)carbamoyl)-2-(difluoromethoxy)-phenoxy)undecanoicacid (77.8 mg, 0.146 mmol) in N,N-dimethylformamide (6 mL) were addedethyldiisopropylamine (57 mg, 0.438 mmol),(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(68 mg, 0.146 mmol), 1-hydroxybenzotriazole (30 mg, 0.219 mmol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (42 mg,0.219 mmol). The mixture was stirred overnight and then concentrated.The residue was purified using prep-TLC eluting withdichloromethane/methanol (15:1) and further purified using prep-HPLC togive(2S,4R)-1-((S)-2-(11-(5-((3,5-dichloropyridin-4-yl)carbamoyl)-2-(difluoromethoxy)phenoxy)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methyl-thiazol-5-yl)benzyl)pyrrolidine-2-carboxamideB76 (30.3 mg) in 22% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 10.64 (s, 1H),8.97 (s, 1H), 8.76 (s, 2H), 8.54 (t, J=5.6 Hz, 1H), 7.83 (d, J=10.0 Hz,1H), 7.72 (s, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.42-6.99 (m, 6H), 5.11 (d,J=3.6 Hz, 1H), 4.54 (d, J=8.8 Hz, 1H), 4.52-4.12 (m, 4H), 4.11 (t, J=6.4Hz, 2H), 3.65 (s, 2H), 2.44 (s, 3H), 2.27-2.23 (m, 1H), 2.13-1.89 (m,3H), 1.77-1.74 (m, 2H), 1.47-1.41 (m, 4H), 1.25-1.23 (m, 10H), 0.92 (s,9H); MS (ESI) m/z: 945.1 [½M+H]⁺, 473.3 [½M+H]⁺.

Example 19 Synthesis of5-((4-((5-(2,6-Dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)benzyl)amino)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)pentanamideB78

To a stirred solution of 5-bromopentanoic acid (300 mg, 1.66 mmol) intoluene (6 mL) was added thionyl chloride (988 mg, 8.3 mmol). Themixture was stirred at 100° C. for 2 h and then concentrated to give5-bromopentanoyl chloride (320 mg, crude).

To a stirred solution of 5-bromopentanoyl chloride (1.66 mmol, crude) intetrahydrofuran (10 mL) was added(S)-4-amino-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)isoindoline-1,3-dione(150 mg, 0.36 mmol). The mixture was stirred overnight and thenconcentrated. The residue was purified using prep-TLC eluting withpetroleum/ethyl acetate (1:1) to give(S)-5-bromo-N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)pentanamide(200 mg) in 96% yield. MS (ESI) m/z: 581.2 [M+H]⁺, 598.2 [M+NH₄]⁺.

To a stirred solution of(S)-5-bromo-N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)pentanamide(200 mg, 0.34 mmol) in N,N-dimethylformamide (4 mL) were added sodiumazide (45 mg, 0.68 mmol) and potassium iodide (6 mg, 0.034 mmol). Afterstirred at 55° C. overnight, the reaction was quenched with water andthe reaction mixture was extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered, and concentrated to give(S)-5-azido-N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)pentanamide(120 mg, crude). MS (ESI) m/z: 561.2 [M+NH₄]⁺.

To a stirred solution of(S)-5-azido-N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)pentanamide(0.34 mmol, crude) in tetrahydrofuran (10 mL) and water (0.5 mL) wasadded triphenylphosphine (135 mg, 0.52 mmol). The mixture was stirredovernight and then concentrated. The residue was purified using prep-TLCeluting with dichloromethane/methanol (10:1) to give(S)-5-amino-N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)pentanamide(70 mg) in 39% yield. MS (ESI) m/z: 518.2 [M+H]⁺.

To a stirred solution of(S)-5-amino-N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)pentanamide(70 mg, 0.135 mmol) and4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)benzaldehyde(52 mg, 0.135 mmol) in dichloromethane (4 mL) and methanol (1 mL) wereadded sodium cyanoborohydride (26 mg, 0.41 mmol) and acetic acid (1drop). The mixture was stirred overnight and then concentrated. Theresidue was purified using prep-HPLC to give5-((4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)benzyl)amino)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)pentanamideB78 (49.9 mg) in 42% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 9.67 (s, 1H),8.46 (d, J=8.4 Hz, 1H), 8.00 (s, 1H), 7.79 (t, J=8.0 Hz, 1H), 7.56 (d,J=7.2 Hz, 1H), 7.25 (d, J=8.4 Hz, 2H), 7.07 (s, 1H), 6.98-6.91 (m, 4H),5.77 (dd, J=4.0, 10.4 Hz, 1H), 5.27 (s, 2H), 5.01 (dd, J=4.8, 13.2 Hz,1H), 4.36-4.31 (m, 2H), 4.24-4.11 (m, 2H), 4.01 (q, J=6.8 Hz, 2H), 3.72(s, 3H), 3.64 (s, 2H), 3.18 (s, 3H), 2.89-2.83 (m, 1H), 2.60-2.53 (m,3H), 2.46 (t, J=7.2 Hz, 2H), 2.35-2.31 (m, 1H), 2.01-1.96 (m, 1H),1.66-1.61 (m, 2H), 1.52-1.47 (m, 2H), 1.31 (t, J=7.2 Hz, 3H); MS (ESI)m/z: 886.3 [M+H]⁺.

Example 20 Synthesis ofN-(6-(7-(1-(2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)heptyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamideB88

To a stirred solution of 5-bromopentan-1-ol (10.0 g, 59.88 mmol) indichloromethane (100 mL) were added p-toluenesulfonic acid (1.5 g, 5.99mmol) and a solution of 3,4-dihydro-2H-pyran (7.5 g, 89.82 mmol) intetrahydrofuran (50 mL) at 0° C. After stirred at room temperatureovernight, the mixture was diluted with water and extracted withdichloromethane. The combined organic layers were dried over anhydroussodium sulfate, filtered, and concentrated. The residue was purifiedusing silica gel eluting with petroleum ether/ethyl acetate (100:1) togive 2-((5-bromopentyl)oxy)tetrahydro-2H-pyran (11.0 g) in 73% yield. ¹HNMR (400 MHz, CDCl₃) δ 5.30 (s, 1H), 4.96-4.94 (m, 2H), 3.90-3.85 (m,2H), 3.55-3.49 (m, 2H), 1.89-1.73 (m, 5H), 1.64-1.48 (m, 8H).

To a stirred solution of 4-methylpyridine (6.2 g, 66.0 mmol) intetrahydrofuran (100 mL) was added 2.5M n-BuLi in tetrahydrofuran (31.7mL, 79.2 mmol) at −60° C. dropwise. The mixture was stirred at roomtemperature for 1.5 hours. 2-((5-Bromopentyl)oxy)tetrahydro-2H-pyran(11.0 g, 44.0 mmol) in tetrahydrofuran (50 mL) was added at −60° C. Thereaction was stirred at room temperature overnight and then quenchedwith sat. NH₄Cl (aq.)(100 mL). The reaction mixture was extracted withethyl acetate. The combined organic layers were dried over anhydroussodium sulfate, filtered, and concentrated. The residue was purifiedusing silica gel eluting with petroleum ether/ethyl acetate (20:1) togive 4-(6-((tetrahydro-2H-pyran-2-yl)oxy)hexyl)pyridine (9.5 g) in 82%yield. MS (ESI) m/z: 264.2 [M+H]⁺.

To a stirred solution of4-(6-((tetrahydro-2H-pyran-2-yl)oxy)hexyl)pyridine (9.5 g, 36.1 mmol) inethyl acetate (100 mL) was added HCl/EtOAc (20 mL). The mixture wasstirred overnight and then filtered. The filter cake was washed withethyl acetate. The solid was dried under vacuum to give6-(pyridin-4-yl)hexan-1-ol hydrochloride (6.0 g) in 78% yield. MS (ESI)m/z: 180.2 [M+H]⁺.

To a stirred solution of 6-(pyridin-4-yl)hexan-1-ol hydrochloride (6.0g, 27.78 mmol) in ethanol (180 mL) was added platinum dioxide (600 mg)under nitrogen. The mixture was degassed and backfilled with hydrogen.The mixture was stirred overnight under nitrogen and then filtered. Thefiltrate was concentrated to give 6-(piperidin-4-yl)hexan-1-olhydrochloride (6.2 g) in a quantitative yield. MS (ESI) m/z: 186.2[M+H]⁺.

To a stirred solution of 6-(piperidin-4-yl)hexan-1-ol hydrochloride (6.2g, 27.9 mmol) in tetrahydrofuran/water (1:1 80 mL) were addedtriethylamine (5.6 g, 55.9 mmol) and di-tert-butyl dicarbonate (9.1 g,41.9 mmol). The mixture was stirred for 3 h and then extracted withethyl acetate. The combined organic layers were dried over anhydrousNa₂SO₄, filtered, and concentrated. The residue was purified usingsilica gel eluting with petroleum ether/ethyl acetate (20:1) to givetert-butyl 4-(6-hydroxyhexyl)piperidine-1-carboxylate (7.2 g) in 90%yield. ¹H NMR (400 MHz, CDCl₃) δ 4.02 (s, 2H), 3.60 (t, J=6.4 Hz, 2H),2.63 (t, J=12.0 Hz, 2H), 1.77 (s, 1H), 1.62-1.49 (m, 4H), 1.42 (s, 9H),1.36-1.16 (m, 8H), 1.07-0.98 (m, 2H).

To a stirred solution of tert-butyl4-(6-hydroxyhexyl)piperidine-1-carboxylate (2 g, 7.02 mmol) indichloromethane (40 mL) was added Dess-Matin reagent (3.57 g, 8.42mmol). After stirred for 3 h, the mixture was filtered and washed withdichloromethane. The filtrate was concentrated and the residue waspurified using silica gel eluting with methanol in dichloromethane from0% to 10% to give tert-butyl 4-(6-oxohexyl)piperidine-1-carboxylate (1.6g) in 81% yield. ¹H NMR (400 MHz, CDCl₃) δ 9.80 (s, 1H), 4.10 (s, 2H),2.70 (t, J=16.4 Hz, 2H), 2.46 (t, J=9.6 Hz, 2H), 1.69-1.64 (m, 4H), 1.49(s, 9H), 1.36-1.25 (m, 7H), 1.16-1.07 (m, 2H).

To a stirred solution of tert-butyl4-(6-oxohexyl)piperidine-1-carboxylate (1.6 g, 5.65 mmol) and potassiumcarbonate (1.56 g, 11.31 mmol) in methanol (30 mL) was added dimethyl(1-diazo-2-oxopropyl)phosphonate (1.14 g, 5.94 mmol). The mixture wasstirred overnight and then diluted with water (50 mL). The organicsolvent was removed under vacuum. The aqueous phase was extracted withpetroleum ether. The combined organic layers were dried over anhydrousNa₂SO₄, filtered, and concentrated to give tert-butyl4-(hept-6-yn-1-yl)piperidine-1-carboxylate (1.2 g) in 76% yield. ¹H NMR(400 MHz, CDCl₃) δ 4.10 (s, 2H), 2.70-2.63 (m, 2H), 2.18 (m, 2H), 1.94(t, J=2.4 Hz, 1H), 1.65-1.49 (m, 5H), 1.46 (s, 9H), 1.42-1.21 (m, 6H),1.11-1.04 (m, 2H).

To a stirred solution of(S)-N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-6-iodo-1,3-dioxoisoindolin-4-yl)acetamide(1 g, crude), tert-butyl 4-(hept-6-yn-1-yl)piperidine-1-carboxylate (953mg, 3.41 mmol), and triethylamine (517 mg, 5.12 mmol) in tetrahydrofuran(15 mL) were added cuprous iodide (65 mg, 0.341 mmol) and Pd(PPh₃)Cl₂(240 mg, 0.34 mmol) under nitrogen. The mixture was degassed andbackfilled with nitrogen. After stirred at 70° C. for 4 h, the mixturewas diluted with water and extracted with ethyl acetate. The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered, andconcentrated. The residue was purified using silica gel eluting withPE/EtOAc (5:1) to give (S)-tert-butyl4-(7-(7-acetamido-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-5-yl)hept-6-yn-1-yl)piperidine-1-carboxylate(520 mg). MS (ESI) m/z: 638.3 [M+H]⁺.

To a stirred solution of (S)-tert-butyl4-(7-(7-acetamido-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-5-yl)hept-6-yn-1-yl)piperidine-1-carboxylate(520 mg, 0.706 mmol) in MeOH (20 mL) was added Pd/C (100 mg) undernitrogen. The mixture was degassed and backfilled with hydrogen. Themixture was stirred overnight and then filtered. The filtrate wasconcentrated to give (S)-tert-butyl4-(7-(7-acetamido-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-5-yl)heptyl)piperidine-1-carboxylate(470 mg) in 83% yield. MS (ESI) m/z: 642.4 [M+H]⁺.

To a stirred solution of (S)-tert-butyl4-(7-(7-acetamido-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-5-yl)heptyl)piperidine-1-carboxylate(50 mg, 0.068 mmol) in dichloromethane (1.5 mL) was addedtrifluoroacetic acid (0.5 mL). The mixture was stirred for 1 h and thenconcentrated. The residue was dissolved in tetrahydrofuran (2 mL) andthen potassium carbonate (19 mg, 0.14 mmol) was added. The mixture wasstirred for 10 min and then concentrated. The residue was purified usingsilica gel eluting with dichloromethane/methanol (20:1) and furtherpurified using prep-HPLC to afford(S)-N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxo-6-(7-(piperidin-4-yl)heptyl)isoindolin-4-yl)acetamide(43 mg) in a quantitative yield. MS (ESI) m/z: 642.4 [M+H]⁺.

To a stirred solution of(S)-N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxo-6-(7-(piperidin-4-yl)heptyl)isoindolin-4-yl)acetamide(43 mg, 0.067 mmol) and DIPEA (22 mg, 0.168 mmol) in N-methylpyrrolidone(2 mL) was added2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (6) (22 mg,0.081 mmol) under nitrogen. After heated at 150° C. under microwave for2.5 h, the mixture was poured into ethyl acetate (25 mL) and then washedwith 1M LiCl aqueous solution. The combined organic layers were driedover anhydrous Na₂SO₄, filtered, and concentrated. The residue waspurified using silica gel eluting with methanol in dichloromethane from0% to 10% and further purified using prep-HPLC to affordN-(6-(7-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)heptyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide(15.5 mg) B88 in 26% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H),9.64 (s, 1H), 8.28 (s, 1H), 7.66 (t, J=7.6 Hz, 1H), 7.43 (s, 1H),7.33-7.30 (m, 2H), 7.06 (s, 1H), 6.96-6.91 (m, 2H), 5.75 (dd, J=10.8 Hz,4.4 Hz, 1H), 5.08 (dd, J=12.8 Hz, 5.2 Hz, 1H), 4.34-4.30 (m, 1H),4.15-4.11 (m, 1H), 4.01 (q, J=6.8 Hz, 2H), 3.73 (s, 3H), 3.67 (d, J=12.4Hz, 2H), 3.01 (s, 3H), 2.86-2.80 (m, 3H), 2.73-2.70 (m, 2H), 2.54-2.50(m, 2H), 2.17 (s, 3H), 2.03-1.98 (m, 2H), 1.74 (d, J=12.0 Hz, 2H),1.60-1.57 (m, 2H), 1.33-1.30 (m, 15H); MS (ESI) m/z: 898.4 [M+H]⁺.

Example 21 Synthesis of3-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)propanamideB89

To a stirred solution of tert-butyl (2-(2-hydroxyethoxy)ethyl)carbamate(2 g, 9.76 mmol) in toluene (20 mL) were added ethyl acrylate (2.928 g,29.28 mmol) and cesium carbonate (6.344 g, 19.52 mmol). After stirred at50° C. overnight, the mixture was concentrated, diluted with H₂O, andextracted with ethyl acetate. The combined organic layers wereconcentrated. The residue was purified using silica gel eluting withethyl acetate in petroleum ether from 0 to 50% to give ethyl2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatetradecan-14-oate (948 mg) in 32%yield.

To a stirred solution of ethyl2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatetradecan-14-oate (948 mg, 3.11mmol) in tetrahydrofuran (8 mL), methanol (2 mL), and H₂O (2 mL) at 0°C. was added lithium hydroxide (266 mg, 6.22 mmol). After stirred atroom temperature overnight, the mixture was concentrated, diluted withH₂O, and extracted with methyl tert-butyl ether. The aqueous phase wasacidified to pH 5-6 with 1N hydrochloric acid and extracted with ethylacetate. The combined organic layers were dried over anhydrous sodiumsulfate, filtered, and concentrated to give2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatetradecan-14-oic acid (644 mg) in74% yield. MS (ESI) m/z: 275 [M−H]⁺.

To a stirred solution of2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatetradecan-14-oic acid (644 mg,2.32 mmol) in dichloromethane (8 mL) at 0° C. were added oxalyl chloride(359 mg, 2.78 mmol) and 1 drop of N,N-dimethylformamide. The mixture wasstirred at room temperature for 1 h and then concentrated to givetert-butyl (2-(2-(3-chloro-3-oxopropoxy)ethoxy)ethyl)carbamate (650 mg,crude).

To a stirred solution of tert-butyl(2-(2-(3-chloro-3-oxopropoxy)ethoxy)ethyl)-carbamate (2.32 mmol, crude)in tetrahydrofuran (3 mL) was added(S)-4-amino-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)isoindoline-1,3-dione(388 mg, 0.93 mmol). The mixture was stirred overnight and thenconcentrated. The residue was purified using prep-TLC eluting withdichloromethane/methanol (10:1) to give(S)-14-amino-N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)-3,6,9,12-tetraoxatetradecan-1-amide(35 mg) in 7% yield. MS (ESI) m/z: 578.2 [M+H]⁺.

To a stirred solution of((S)-14-amino-N-(2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)-3,6,9,12-tetraoxatetradecan-1-amide(35 mg, 0.06 mmol) and2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (33 mg, 0.12mmol) in N,N-dimethylformamide (3 mL) was addedN,N-diisopropylethylamine (23 mg, 0.18 mmol). The mixture was stirred at150° C. for 1 h under microwave. Water was added and the mixture wasextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered, andconcentrated. The residue was purified using prep-TLC eluting with ethylacetate to give3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)propanamideB89 (16.3 mg) in 33% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H),9.87 (s, 1H), 8.52 (d, J=8.4 Hz, 1H), 7.75 (t, J=7.6 Hz, 1H), 7.53-7.48(m, 2H), 7.10-7.05 (m, 1H), 6.99-6.97 (m, 3H), 6.92 (d, J=8.0 Hz, 1H),6.53 (t, J=5.6 Hz, 1H), 5.77 (dd, J=4.4, 10.8 Hz, 1H), 5.03 (dd, J=5.2,12.4 Hz, 1H), 4.36-4.30 (m, 1H), 4.14 (dd, J=4.4, 14.8 Hz, 1H), 4.01 (q,J=6.4 Hz, 2H), 3.76-3.75 (m, 2H), 3.72 (s, 3H), 3.61-3.57 (m, 6H), 3.01(s, 3H), 2.91-2.82 (m, 1H), 2.69-2.65 (m, 2H), 2.59-2.55 (m, 1H),2.45-2.43 (m, 2H), 2.05-1.98 (m, 2H), 1.31 (t, J=6.8 Hz, 3H); MS (ESI)m/z: 834.3 [M+H]⁺.

Example 22 SynthesisofN-(3,5-Dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-((4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)benzyl)amino)heptyl)oxy)benzamideB92

To a solution of tert-butyl5-amino-4-(1-(hydroxymethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-5-oxopentanoate(650 mg, 1.84 mmol) in dichloromethane (20 mL) at 0° C. was addedtriethylamine (371 mg, 3.68 mmol), followed by addition ofmethanesulfonyl chloride (420 mg, 3.68 mmol). The mixture was stirredovernight and then concentrated. The residue was purified using silicagel eluting with ethyl acetate in petroleum ether from 10% to 70% togive tert-butyl5-amino-4-(1-(chloromethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-5-oxopentanoateve(458 mg) in 67% yield. MS (ESI) m/z: 373.1 [M+H]⁺.

To a solution of tert-butyl5-amino-4-(1-(chloromethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-5-oxopentanoateve(423 mg, 1.14 mmol) in N,N-dimethylformamide (20 mL) were addedtert-butyl 4-hydroxybenzylcarbamate (304 mg, 1.36 mmol) and potassiumcarbonate (314 mg, 2.28 mmol). After heated at 80° C. for 2 h, themixture was diluted with H₂O and extracted with ethyl acetate. Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered, andconcentrated. The residue was purified using silica gel eluting withethyl acetate in petroleum ether from 10% to 80% to give tert-butyl5-amino-4-(1-((4-(((tert-butoxycarbonyl)amino)methyl)-phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-5-oxopentanoate(576 mg) in 91% yield. MS (ESI) m/z: 560.2 [M+H]⁺.

To a solution of tert-butyl5-amino-4-(1-((4-(((tert-butoxycarbonyl)amino)methyl)-phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-5-oxopentanoate(576 mg, 1.03 mmol) in tetrahydrofuran/H₂O (15 mL/15 mL) was addedLiOH.H₂O (46 mg, 1.03 mmol). The mixture was stirred overnight and thenconcentrated. The residue was acidified to pH 5 with 2N HCl and thenextracted with dichloromethane/methanol (10:1). The combined organiclayers were dried over anhydrous Na₂SO₄, filtered, and concentrated togive5-amino-4-(1-((4-(((tert-butoxycarbonyl)-amino)methyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-5-oxopentanoicacid (359 mg) in 69% yield. MS (ESI) m/z: 504.2 [M+H]⁺.

To a solution of5-amino-4-(1-((4-(((tert-butoxycarbonyl)amino)methyl)phenoxy)-methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-5-oxopentanoicacid (359 mg, 0.714 mmol) in acetonitrile (20 mL) was added1,1′-carbonyldiimidazole (346 mg, 2.14 mmol). The mixture was stirred at95° C. for 4 h. The resulting solid was filtered and dried under vacuumto give tert-butyl4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)-benzylcarbamate(197 mg). The filtrate was concentrated and the residue was purifiedusing silica gel eluting with ethyl acetate in petroleum ether from 10%to 70% to give additional tert-butyl4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)benzylcarbamate(108 mg). The combined total of the desired product was 305 mg (88%yield). MS (ESI) m/z: 486.2 [M+H]⁺.

To a solution of tert-butyl4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)benzylcarbamate(44 mg, 0.091 mmol) in dichloromethane (4 mL) was added trifluoroaceticacid (1 mL). The mixture was stirred for 1 h and then concentrated togive3-(1-((4-(aminomethyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione(35 mg, crude). MS (ESI) m/z: 386.1[M+H]⁺.

To a solution ofN-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-(methoxy(methyl)amino)-7-oxoheptyl)oxy)benzamide(80 mg, 0.15 mmol) in tetrahydrofuran (5 mL) at −70° C. under N₂ wasadded LiAlH₄ (0.31 mL, 1 M in THF). After stirred at this temperaturefor 30 min, the reaction was quenched with sat. NH₄Cl (5 mL) and thereaction mixture was extracted with ethyl acetate. The combined organiclayers were dried over anhydrous Na₂SO₄, filtered, and concentrated togiveN-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-oxoheptyl)oxy)benzamide(75 mg, crude). MS (ESI) m/z: 461.1 [M+H]⁺.

To a solution ofN-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-oxoheptyl)oxy)benzamide(54 mg, 0.12 mmol) in dichloromethane/methanol (4 mL/1 mL) were added3-(1-((4-(aminomethyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione(35 mg, crude) and N,N-diisopropylethylamine (12 mg, 0.09 mmol),followed by addition of NaBH₃CN (18 mg, 0.27 mmol). The mixture wasstirred overnight and then concentrated. The residue was purified usingsilica gel eluting with methanol in dichloromethane from 0% to 10% andfurther purified using prep-HPLC to giveN-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-((4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)benzyl)-amino)heptyl)oxy)benzamideB92 (21.7 mg) in 28.9% yield. ¹H NMR (400 MHz, DMSO-d₆) δ 8.70 (s, 2H),8.01 (s, 1H), 7.72 (d, J=1.6 Hz, 1H), 7.65 (dd, J=2.0, 8.8 Hz, 1H),7.35-7.32 (m, 1H), 7.26-7.24 (m, 2H), 7.17 (s, 1H), 6.98-6.95 (m, 2H),5.28 (s, 2H), 5.01 (dd, J=5.3, 13.2 Hz, 1H), 4.37-4.20 (m, 2H), 4.10 (t,J=6.4 Hz, 2H), 3.64 (s, 2H), 3.52-3.48 (m, 2H), 2.93-2.84 (m, 1H),2.60-2.55 (m, 2H), 2.39-2.29 (m, 1H), 2.00-1.95 (m, 1H), 1.79-1.73 (m,2H), 1.45-1.41 (m, 4H), 1.32-1.31 (m, 4H); MS (ESI) m/z: 832.2 [M+H]⁺.

The following compounds were prepared similarly according to thesynthetic procedures or methodologies exemplified herein.

-   3-(Cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-N-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)benzamide    B3. ¹H NMR (400 MHz, DMSO-d₆) δ 11.06 (s, 1H), 10.57 (s, 1H), 9.12    (s, 1H), 8.72 (s, 2H), 7.43 (d, J=6.8 Hz, 1H), 7.29-7.28 (m, 1H),    7.11-6.86 (m, 4H), 5.17 (dd, J=5.2, 13.2 Hz, 1H), 4.58-4.35 (m, 2H),    3.74-3.72 (m, 2H), 3.59-3.54 (m, 2H), 3.12-3.11 (m, 2H), 2.99-2.92    (m, 4H), 2.65-2.57 (m, 1H), 2.37-2.31 (m, 1H), 2.20-2.13 (m, 1H),    2.06-1.98 (m, 2H), 1.72-1.71 (m, 2H), 1.60-1.59 (m, 2H), 1.31-1.26    (m, 10H), 1.14-1.11 (m, 1H), 0.56-0.54 (m, 2H), 0.30-0.29 (m, 2H);    MS (ESI) m/z: 844.3 [M+H]⁺.

-   3-(2-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)-ethoxy)ethoxy)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)propanamide    B43. ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 9.86 (s, 1H), 8.53    (d, J=8.4 Hz, 1H), 7.78 (t, J=8.0 Hz, 1H), 7.56-7.52 (m, 2H),    7.09-7.07 (m, 2H), 7.02-6.92 (m, 3H), 6.56 (t, J=6.0 Hz, 1H), 5.78    (dd, J=4.0, 10.4 Hz, 1H), 5.05 (dd, J=5.2, 12.8 Hz, 1H), 4.37-4.31    (m, 1H), 4.17-4.12 (m, 1H), 4.01 (q, J=7.2 Hz, 2H), 3.72-3.71 (m,    5H), 3.56-3.55 (m, 6H), 3.49 (s, 4H), 3.43-3.40 (m, 2H), 3.01 (s,    3H), 2.89-2.84 (m, 1H), 2.69 (t, J=6.0 Hz, 2H), 2.61-2.53 (m, 2H),    2.04-2.01 (m, 1H), 1.31 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 878.3    [M+H]⁺.

-   N-(3,5-Dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((9-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)nonyl)oxy)benzamide    B45. ¹H NMR (400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 10.73 (s, 1H), 10.32    (s, 1H), 8.77 (s, 2H), 7.75 (d, J=1.6 Hz, 1H), 7.67 (dd, J=1.6, 8.0    Hz, 1H), 7.43 (dd, J=1.6, 7.6 Hz, 1H), 7.39-7.02 (m, 3H), 5.17 (dd,    J=5.2, 13.2 Hz, 1H), 4.58-4.35 (m, 2H), 4.13 (t, J=6.4 Hz, 2H),    3.60-3.50 (m, 2H), 3.07-2.89 (m, 6H), 2.67-2.57 (m, 1H), 2.39-2.33    (m, 1H), 2.07-1.96 (m, 5H), 1.81-1.69 (m, 4H), 1.47-1.44 (m, 2H),    1.33-1.29 (m, 8H); MS (ESI) m/z: 819.7 [M+H]⁺.

-   N-(3,5-Dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((5-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)pentyl)oxy)benzamide    B46. ¹H NMR (400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 10.67 (s, 1H), 9.18    (s, 1H), 8.77 (s, 2H), 7.73-7.68 (m, 2H), 7.45-7.37 (m, 2H),    7.31-6.95 (m, 2H), 5.17 (dd, J=5.2, 13.2 Hz, 1H), 4.56-4.40 (m, 2H),    4.17 (t, J=6.4 Hz, 2H), 3.62 (d, J=10.4 Hz, 2H), 3.15-3.10 (m, 2H),    3.04-2.93 (m, 4H), 2.66-2.61 (m, 1H), 2.35-2.27 (m, 1H), 2.06-2.03    (m, 3H), 1.89-1.74 (m, 6H), 1.54-1.47 (m, 2H); MS (ESI) m/z: 764.2    [M+H]⁺.

-   3-(6-Fluoro-4-(1-(7-(2-methoxy-5-(1-oxoisoindolin-2-yl)phenoxy)heptyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione    B49. ¹H NMR (400 MHz, DMSO-d₆) δ 11.01 (s, 1H), 7.75 (d, J=7.6 Hz,    1H), 7.68-7.64 (m, 3H), 7.56-7.52 (m, 1H), 7.39 (dd, J=2.0, 12.0 Hz,    1H), 7.34 (dd, J=2.4, 7.6 Hz, 1H), 7.28 (dd, J=2.8, 8.8 Hz, 1H),    7.01 (d, J=8.4 Hz, 1H), 5.14 (dd, J=4.8, 12.8 Hz, 1H), 4.99 (s, 2H),    4.52-4.31 (m, 2H), 3.99 (t, J=6.8 Hz, 2H), 3.77 (s, 3H), 2.99-2.87    (m, 3H), 2.62-2.58 (m, 2H), 2.45-2.41 (m, 1H), 2.33-2.29 (m, 2H),    2.04-1.94 (m, 3H), 1.79-1.67 (m, 6H), 1.48-1.30 (m, 8H); MS (ESI)    m/z: 697.4 [M+H]⁺.

-   3-(4-(1-(7-(2-(Cyclopentyloxy)-4-(1-oxoisoindolin-2-yl)phenoxy)heptyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione    B50. ¹H NMR (400 MHz, DMSO-d₆) δ 11.01 (s, 1H), 7.75 (d, J=7.6 Hz,    1H), 7.68-7.65 (m, 3H), 7.55-7.53 (m, 1H), 7.39-7.33 (m, 2H),    7.27-7.24 (m, 1H), 7.00 (d, J=8.8 Hz, 1H), 5.13 (dd, J=5.2, 13.2 Hz,    1H), 4.97 (s, 2H), 4.82-4.80 (m, 1H), 4.52-4.31 (m, 2H), 3.95 (t,    J=6.4 Hz, 2H), 2.96-2.92 (m, 3H), 2.62-2.58 (m, 2H), 2.47-2.41 (m,    1H), 2.28 (t, J=7.2 Hz, 2H), 2.03-1.85 (m, 5H), 1.78-1.64 (m, 10H),    1.60-1.56 (m, 2H), 1.44-1.38 (m, 4H), 1.35-1.29 (m, 4H); MS (ESI)    m/z: 751.4 [M+H]⁺.

-   2-(3-((7-(4-(2-(2,6-Dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)oxy)-4-methoxyphenyl)isoindoline-1,3-dione    B51. ¹H NMR (400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 9.41 (s, 1H),    7.96-7.91 (m, 4H), 7.43 (d, J=7.2 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H),    7.10-7.08 (m, 2H), 6.97 (d, J=7.6 Hz, 1H), 5.17 (dd, J=5.2, 13.2 Hz,    1H), 4.56-4.36 (m, 2H), 3.95 (t, J=6.4 Hz, 2H), 3.83 (s, 3H),    3.61-3.59 (m, 2H), 3.09-2.92 (m, 6H), 2.66-2.62 (m, 1H), 2.37-2.33    (m, 1H), 2.08-1.93 (m, 5H), 1.77-1.69 (m, 4H), 1.45-1.24 (m, 6H); MS    (ESI) m/z: 711.3 [M+H]⁺.

-   5-Amino-2-(3-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)oxy)-4-methoxyphenyl)isoindoline-1,3-dione    B52. ¹H NMR (400 MHz, DMSO-d₆) δ 11.06 (s, 1H), 7.54 (s, 1H), 7.41    (s, 1H), 7.31 (s, 1H), 7.02 (s, 3H), 6.89 (s, 2H), 6.66 (s, 2H),    5.18-5.14 (m, 1H), 4.61-4.35 (m, 2H), 3.94 (s, 2H), 3.81 (s, 3H),    3.09-2.92 (m, 6H) 2.37-2.33 (m, 5H), 2.08-1.99 (m, 4H), 1.77-1.69    (m, 4H), 1.42-1.25 (m, 6H); MS (ESI) m/z: 726.3 [M+H]⁺.

-   3-(6-Fluoro-4-(1-(7-(2-methoxy-5-(5-oxopyrrolidin-3-yl)phenoxy)heptyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione    B53. ¹H NMR (400 MHz, DMSO-d₆) δ 11.01 (s, 1H), 7.66 (s, 1H), 7.40    (dd, J=2.4, 10.8 Hz, 1H), 7.34 (dd, J=2.0, 7.2 Hz, 1H), 6.91-6.86    (m, 2H), 6.78 (dd, J=2.0, 8.0 Hz, 1H), 5.13 (dd, J=4.8, 13.2 Hz,    1H), 4.52-4.31 (m, 2H), 3.94 (t, J=6.8 Hz, 2H), 3.72 (s, 3H),    3.55-3.49 (m, 2H), 3.18-3.14 (m, 2H), 2.98-2.91 (m, 2H), 2.62-2.58    (m, 2H), 2.50-2.40 (m, 2H), 2.33-2.26 (m, 3H), 2.01-1.90 (m, 3H),    1.73-1.68 (m, 6H), 1.44-1.32 (m, 8H); MS (ESI) m/z: 649.3 [M+H]⁺.

-   2-(3-(Cyclopentyloxy)-4-methoxyphenyl)-5-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)amino)isoindoline-1,3-dione    B54. ¹H NMR (400 MHz, DMSO-d₆) δ 11.01 (s, 1H), 7.59 (d, J=8.4 Hz,    1H), 7.40-7.36 (m, 2H), 7.08 (t, J=5.2 Hz, 1H), 7.02-6.95 (m, 3H),    6.88-6.84 (m, 2H), 5.13 (dd, J=5.2, 13.2 Hz, 1H), 4.73-4.70 (m, 1H),    4.52-4.30 (m, 2H), 3.78 (s, 3H), 3.19-3.14 (m, 3H), 2.96-2.87 (m,    3H), 2.61-2.55 (m, 2H), 2.44-2.40 (m, 1H), 2.28 (t, J=7.2 Hz, 2H),    2.02-1.94 (m, 3H), 1.72-1.68 (m, 8H), 1.58-1.55 (m, 4H), 1.46-1.31    (m, 9H); MS (ESI) m/z: 794.4 [M+H]⁺.

-   3-(6-Fluoro-5-(1-(7-(2-methoxy-5-(5-oxopyrrolidin-3-yl)phenoxy)heptyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione    B55. ¹H NMR (400 MHz, DMSO-d₆) δ 11.00 (s, 1H), 7.66 (s, 1H), 7.40    (dd, J=2.4, 10.8 Hz, 1H), 7.35 (dd, J=2.0, 7.2 Hz, 1H), 6.91 (d,    J=2.0 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 6.79 (dd, J=2.0, 8.0 Hz, 1H),    5.13 (dd, J=4.8, 13.2 Hz, 1H), 4.43-4.26 (m, 2H), 3.94 (t, J=6.8 Hz,    2H), 3.72 (s, 3H), 3.57-3.47 (m, 2H), 3.18-3.14 (m, 1H), 2.98-2.90    (m, 2H), 2.62-2.57 (m, 2H), 2.49-2.40 (m, 1H), 2.32-2.26 (m, 5H),    2.02-1.93 (m, 3H), 1.73-1.68 (m, 6H), 1.44-1.32 (m, 8H); MS (ESI)    m/z: 649.3 [M+H]⁺.

-   3-(4-(1-(7-((2-(3-(Cyclopentyloxy)-4-methoxyphenyl)-3-oxoisoindolin-5-yl)amino)heptyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione    B56. ¹H NMR (400 MHz, DMSO-d₆) δ 11.01 (s, 1H), 7.67 (d, J=2.4 Hz,    1H), 7.40-7.30 (m, 3H), 7.20 (dd, J=2.0, 8.8 Hz, 1H), 6.96 (d, J=8.4    Hz, 1H), 6.88 (dd, J=1.6, 8.0 Hz, 1H), 6.81 (s, 1H), 5.91 (t, J=10.0    Hz, 1H), 5.12 (dd, J=4.8, 13.2 Hz, 1H), 4.77 (s, 3H), 4.52-4.35 (m,    2H), 3.74 (s, 3H), 3.07-3.02 (m, 2H), 2.97-2.91 (m, 3H), 2.62-2.58    (m, 2H), 2.45-2.42 (m, 1H), 2.28 (t, J=6.8 Hz, 2H), 2.03-1.91 (m,    5H), 1.73-1.68 (m, 8H), 1.57-1.54 (m, 4H), 1.38-1.31 (m, 8H); MS    (ESI) m/z: 780.5 [M+H]⁺.

-   3-(4-(1-(7-(2-(Cyclopentyloxy)-4-(5-oxopyrrolidin-3-yl)phenoxy)heptyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione    B57. ¹H NMR (400 MHz, DMSO-d₆) δ 11.01 (s, 1H), 7.67 (s, 1H),    7.40-7.35 (m, 2H), 6.87 (d, J=4.0 Hz, 2H), 6.78 (d, J=8.0 Hz, 1H),    5.12 (dd, J=4.8, 13.2 Hz, 1H), 4.78 (s, 1H), 4.54-4.32 (m, 2H), 3.91    (t, J=6.0 Hz, 2H), 3.16 (t, J=7.6 Hz, 2H), 2.99-2.89 (m, 6H),    2.64-2.59 (m, 2H), 2.48-2.44 (m, 1H), 2.33-2.24 (m, 3H), 2.04-1.98    (m, 4H), 1.81-1.71 (m, 10H), 1.60-1.54 (m, 2H), 1.46-1.31 (m, 8H);    MS (ESI) m/z: 703.4 [M+H]⁺.

-   5-Amino-2-(3-(cyclopentyloxy)-4-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)oxy)phenyl)isoindoline-1,3-dione    B58. ¹H NMR (400 MHz, DMSO-d₆) δ 11.06 (s, 1H), 9.41 (s, 1H), 7.55    (d, J=8.4 Hz, 1H), 7.44 (d, J=7.2 Hz, 1H), 7.32 (d, J=10.4 Hz, 1H),    7.03 (d, J=8.8 Hz, 1H), 6.98 (s, 2H), 6.86 (d, J=8.4 Hz, 2H), 5.16    (dd, J=4.8, 13.6 Hz, 1H), 4.74 (s, 1H), 4.56-4.36 (m, 2H), 4.00 (t,    J=6.0 Hz, 1H), 3.60-3.47 (m, 3H), 3.09-2.89 (m, 8H), 2.66-2.60 (m,    1H), 2.40-2.29 (m, 1H), 2.07-1.89 (m, 5H), 1.83-1.72 (m, 10H),    1.62-1.58 (m, 2H), 1.47-1.37 (m, 6H); MS (ESI) m/z: 780.4 [M+H]⁺.

-   3-(4-(1-(7-(5-(6-Amino-1-oxoisoindolin-2-yl)-2-methoxyphenoxy)heptyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione    B60. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 9.22 (s, 1H), 7.71    (s, 1H), 7.44 (dd, J=2.0, 7.2 Hz, 1H), 7.31-7.28 (m, 2H), 7.23-7.19    (m, 1H), 7.01-6.97 (m, 1H), 6.94-6.90 (m, 2H), 5.18 (dd, J=4.8 Hz,    13.2 Hz, 1H), 4.79 (s, 2H), 4.55-4.35 (m, 2H), 3.99 (t, J=6.0 Hz,    2H), 3.77 (s, 3H), 3.13-3.08 (m, 2H), 3.02-2.90 (m, 3H), 2.66-2.60    (m, 2H), 2.35-2.31 (m, 2H), 2.09-1.92 (m, 5H), 1.80-1.75 (m, 2H),    1.72-1.66 (m, 2H), 1.49-1.34 (m, 8H); MS (ESI) m/z: 712.4 [M+H]⁺.

-   3-(4-(1-(7-(5-(6-Amino-1-oxoisoindolin-2-yl)-2-methoxyphenoxy)heptyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione    B62. ¹H NMR (400 MHz, DMSO-d₆) δ 11.06 (s, 1H), 8.80 (s, 1H), 7.58    (s, 1H), 7.44-7.38 (m, 2H), 7.31 (d, J=8.0 Hz, 1H), 7.09 (d, J=8.8    Hz, 1H), 6.89 (dd, J=1.6, 8.0 Hz, 1H), 6.82-6.80 (m, 2H), 5.92 (s,    1H), 5.16 (dd, J=3.6, 13.2 Hz, 1H), 4.78-4.75 (m, 3H), 4.56-4.35 (m,    2H), 4.23-4.19 (m, 2H), 3.19-3.17 (m, 2H), 3.07-3.04 (m, 2H),    2.99-2.92 (m, 4H), 2.65-2.62 (m, 1H), 2.42-2.35 (m, 1H), 2.06-1.87    (m, 8H), 1.79-1.74 (m, 4H), 1.64-1.54 (m, 4H), 1.48-1.29 (m, 8H); MS    (ESI) m/z: 766.5 [M+H]⁺.

-   3-((4-((2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)-methyl)benzyl)oxy)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)propanamide    B64. ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 9.90 (s, 1H), 8.52    (d, J=8.0 Hz, 1H), 7.79 (t, J=8.0 Hz, 1H), 7.58-7.53 (m, 2H),    7.29-7.23 (m, 4H), 7.13-7.08 (m, 2H), 7.03 (d, J=7.2 Hz, 1H),    6.98-6.91 (m, 2H), 6.64 (t, J=6.0 Hz, 1H), 5.78 (dd, J=4.4, 10.4 Hz,    1H), 5.06 (dd, J=5.2, 12.8 Hz, 1H), 4.53 (s, 2H), 4.48 (s, 2H),    4.36-4.30 (m, 1H), 4.16-4.12 (m, 1H), 3.99 (q, J=6.4 Hz, 2H),    3.74-3.72 (m, 5H), 3.61-3.58 (m, 2H), 3.51-3.47 (m, 2H), 3.00 (s,    3H), 2.88-2.85 (m, 1H), 2.74 (t, J=6.0 Hz, 2H), 2.61-2.53 (m, 2H),    2.04-2.01 (m, 1H), 1.29 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 910.3    [M+H]⁺.

-   2-(2,6-Dioxopiperidin-3-yl)-4-((7-(2-methoxy-5-(5-oxopyrrolidin-3-yl)phenoxy)-heptyl)amino)isoindoline-1,3-dione    B66. ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 7.66 (s, 1H), 7.58    (t, J=7.6 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 7.02 (d, J=6.0 Hz, 1H),    6.91-6.86 (m, 2H), 6.79-6.77 (m, 1H), 6.54 (s, 1H), 5.05 (dd, J=5.2,    12.8 Hz, 1H), 3.94 (t, J=8.8 Hz, 1H), 3.71 (s, 3H), 3.58-3.47 (m,    3H), 3.31-3.29 (m, 2H), 3.18-3.14 (m, 1H), 2.92-2.83 (m, 1H),    2.60-2.56 (m, 1H), 2.47-2.42 (m, 1H), 2.33-2.26 (m, 1H), 2.05-1.97    (m, 1H), 1.71-1.69 (m, 2H), 1.60-1.57 (m, 2H), 1.45-1.35 (m, 6H); MS    (ESI) m/z: 577.3 [M+H]⁺.

-   (2S,4R)-4-Hydroxy-1-((2S)-2-(9-(2-methoxy-5-(5-oxopyrrolidin-3-yl)phenoxy)-nonanamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide    B67. ¹H NMR (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.58 (s, 1H), 7.86    (d, J=8.0 Hz, 1H), 7.68 (s, 1H), 7.44-7.38 (m, 4H), 6.91-6.86 (m,    2H), 6.89 (d, J=8.0 Hz, 1H), 5.17 (s, 1H), 4.55 (d, J=8.8 Hz, 1H),    4.46-4.21 (m, 1H), 4.25-4.20 (m, 1H), 3.93 (t, J=6.0 Hz, 2H), 3.72    (s, 3H), 3.67 (s, 2H), 3.59-3.52 (m, 3H), 3.17 (t, J=7.2 Hz, 1H),    2.51-2.50 (m, 2H), 2.45 (s, 3H), 2.33-2.26 (m, 2H), 2.14-2.02 (m,    2H), 1.98-1.89 (m, 1H), 1.69-1.67 (m, 2H), 1.51-1.28 (m, 10H), 0.94    (s, 9H); MS (ESI) m/z: 776.4 [M+H]⁺.

-   9-((4-((5-(2,6-Dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)benzyl)amino)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)nonanamide    B70. ¹H NMR (400 MHz, DMSO-d₆) δ 9.66 (s, 1H), 8.46 (d, J=8.4 Hz,    1H), 8.00 (s, 1H), 7.78 (t, J=8.0 Hz, 1H), 7.56 (d, J=7.6 Hz, 1H),    7.22 (d, J=8.0 Hz, 2H), 7.07 (s, 1H), 6.98-6.91 (m, 4H), 5.78-5.75    (m, 1H), 5.27 (s, 2H), 5.01 (dd, J=4.8, 13.2 Hz, 1H), 4.36-4.30 (m,    2H), 4.23-4.11 (m, 2H), 4.01 (q, J=7.2 Hz, 2H), 3.72 (s, 3H), 3.58    (s, 2H), 3.04 (s, 3H), 2.91-2.85 (m, 1H), 2.60-2.54 (m, 1H),    2.47-2.40 (m, 4H), 2.35-2.31 (m, 1H), 2.00-1.96 (m, 2H), 1.62-1.58    (m, 2H), 1.40-1.35 (m, 2H), 1.33-1.29 (m, 6H), 1.28-1.24 (m, 5H); MS    (ESI) m/z: 942.4 [M+H]⁺.

-   N-(3,5-Dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptyl)oxy)benzamide    B72. ¹H NMR (400 MHz, DMSO-d₆) δ 11.02 (s, 1H), 10.72 (brs, 1H),    8.77 (s, 2H), 7.74 (s, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.41-7.00 (m,    4H), 5.15 (dd, J=3.6, 12 Hz, 1H), 4.54-4.33 (m, 2H), 4.17-4.07 (m,    2H), 3.03-2.90 (m, 3H), 2.64-2.60 (m, 2H), 2.47-2.43 (m, 1H),    2.36-2.24 (m, 2H), 2.09-1.92 (m, 4H), 1.85-1.63 (m, 6H), 1.54-1.45    (m, 4H), 1.44-1.27 (m, 14H); MS (ESI) m/z: 718.2 [M+H]⁺.

-   N-(3,5-Dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((12-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)dodecyl)oxy)benzamide    B73. ¹H NMR (400 MHz, DMSO-d₆) δ 11.02 (s, 1H), 10.72 (brs, 1H),    8.77 (s, 2H), 7.74 (s, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.41-7.00 (m,    4H), 5.15 (dd, J=3.6, 12 Hz, 1H), 4.54-4.33 (m, 2H), 4.17-4.07 (m,    2H), 3.03-2.90 (m, 3H), 2.64-2.60 (m, 2H), 2.47-2.43 (m, 1H),    2.36-2.24 (m, 2H), 2.09-1.92 (m, 4H), 1.85-1.63 (m, 6H), 1.54-1.45    (m, 4H), 1.44-1.27 (m, 14H); MS (ESI) m/z: 860.3 [M+H]⁺.

-   N-(3,5-Dichloropyridin-4-yl)-3-(difluoromethoxy)-4-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)ethoxy)benzamide    B74. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 10.66 (s, 1H), 8.76    (s, 2H), 7.76 (s, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.57 (t, J=8.0 Hz,    1H), 7.37 (t, J=10.4 Hz, 1H), 7.21 (s, 1H), 7.12 (d, J=8.4 Hz, 1H),    7.03 (d, J=6.8 Hz, 1H), 6.59 (t, J=5.6 Hz, 1H), 5.05 (dd, J=5.2,    12.8 Hz, 1H), 4.28-4.22 (m, 2H), 3.79-3.76 (m, 2H), 3.63-3.58 (m,    4H), 3.56-3.51 (m, 6H), 3.46-3.44 (m, 2H), 2.91-2.84 (m, 1H),    2.60-2.54 (m, 2H), 2.03-1.96 (m, 1H); MS (ESI) m/z: 780.1 [M+H]⁺.

-   9-(4-(2-(2,6-Dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)nonanamide    B77. ¹H NMR (400 MHz, DMSO-d₆) δ 11.00 (s, 1H), 9.68 (s, 1H), 8.46    (d, J=8.4 Hz, 1H), 7.79 (t, J=8.0 Hz, 1H), 7.56 (d, J=7.2 Hz, 1H),    7.39-7.34 (m, 2H), 7.08 (s, 1H), 6.99-6.92 (m, 2H), 5.78 (dd, J=4.0,    10.4 Hz, 1H), 5.13 (dd, J=5.2, 13.2 Hz, 1H), 4.52-4.31 (m, 3H), 4.14    (dd, J=4.0, 14.0 Hz, 1H), 4.02 (q, J=6.8 Hz, 2H), 3.73 (s, 3H), 3.01    (s, 3H), 2.95-2.87 (m, 3H), 2.63-2.58 (m, 2H), 2.47-2.45 (m, 2H),    2.26 (t, J=6.4 Hz, 2H), 2.03-1.91 (m, 3H), 1.71-1.61 (m, 6H),    1.47-1.41 (m, 2H), 1.34-1.30 (m, 12H); MS (ESI) m/z: 902.4 [M+H]⁺.

-   N-(6-(12-(4-(2-(2,6-Dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)dodecyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide    B79. ¹H NMR (400 MHz, DMSO-d₆) δ 11.02 (s, 1H), 9.65 (s, 1H), 8.28    (s, 1H), 7.43-7.35 (m, 3H), 7.07 (s, 1H), 6.97-6.95 (m, 2H), 5.77    (d, J=10.4 Hz, 1H), 5.16-5.13 (m, 1H), 4.54-4.33 (m, 3H), 4.15-4.12    (m, 1H), 4.03-4.01 (m, 2H), 3.75-3.70 (m, 4H), 3.02-2.88 (m, 7H),    2.76-2.69 (m, 2H), 2.64-2.59 (m, 2H), 2.45-2.38 (m, 1H), 2.31-2.30    (m, 2H), 2.21-2.18 (m, 3H), 2.08-2.00 (m, 4H), 1.81-1.75 (m, 4H),    1.58 (s, 2H), 1.48-1.41 (m, 2H), 1.33-1.25 (m, 16H); MS (ESI) m/z:    972.5 [M+H]⁺.

3-(6-Fluoro-4-(1-(7-(2-methoxy-5-(4-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)phenoxy)heptyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneB80. ¹H NMR (400 MHz, DMSO-d₆) δ 11.00 (s, 1H), 7.70 (d, J=4.8 Hz, 1H),7.50 (s, 1H), 7.39 (d, J=11.2 Hz, 1H), 7.35 (d, J=7.2 Hz, 1H), 7.33 (d,J=5.2 Hz, 1H), 7.15 (d, J=10.0 Hz, 1H), 6.98 (d, J=8.8 Hz, 1H), 5.13(dd, J=4.8, 13.2 Hz, 1H), 5.04 (s, 2H), 4.53-4.32 (m, 2H), 3.97 (t,J=6.4 Hz, 2H), 3.76 (s, 3H), 2.98-2.88 (m, 3H), 2.62-2.58 (m, 2H),2.46-2.42 (m, 1H), 2.29 (t, J=7.2 Hz, 2H), 2.03-1.93 (m, 3H), 1.80-1.72(m, 6H), 1.45-1.31 (m, 8H); MS (ESI) m/z: 703.3 [M+H]⁺.

-   3-(Cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(2-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)propoxy)ethoxy)ethoxy)ethoxy)benzamide    B81. ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 10.41 (s, 1H), 8.74    (s, 2H), 7.64 (dd, J=2.0, 8.4 Hz, 1H), 7.57 (t, J=7.6 Hz, 1H),    7.41-7.39 (m, 1H), 7.13 (d, J=8.8 Hz, 2H), 7.03 (d, J=7.6 Hz, 1H),    6.60 (t, J=5.2 Hz, 1H), 5.23 (dd, J=4.8, 12.4 Hz, 1H), 4.74-4.71 (m,    1H), 4.17 (t, J=3.6 Hz, 2H), 3.77 (t, J=4.4 Hz, 2H), 3.64-3.62 (m,    4H), 3.57-3.55 (m, 5H), 3.48-3.43 (m, 4H), 2.92-2.84 (m, 1H),    2.60-2.56 (m, 1H), 2.45-2.39 (m, 2H), 2.10-1.99 (m, 3H), 1.78-1.75    (m, 1H), 1.66-1.59 (m, 1H); MS (ESI) m/z: 784.2 [M+H]⁺.

-   3-(Cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)oxy)benzamide    B82. ¹H NMR (400 MHz, DMSO-d₆) δ 11.00 (s, 1H), 11.14 (s, 1H), 8.74    (s, 2H), 7.65 (d, J=8.4 Hz, 1H), 7.41-7.34 (m, 3H), 7.12 (d, J=8.4    Hz, 1H), 5.13 (dd, J=4.8, 12.8 Hz, 1H), 4.73 (t, J=7.2 Hz, 1H),    4.52-4.32 (m, 2H), 4.07 (t, J=6.4 Hz, 2H), 2.99-2.87 (m, 2H),    2.60-2.52 (m, 2H), 2.43 (d, J=8.4 Hz, 2H), 2.30 (t, J=6.8 Hz, 2H),    2.10-1.91 (m, 4H), 1.80-1.63 (m, 6H), 1.47-1.24 (m, 13H); MS (ESI)    m/z: 794.3 [M+H]⁺.

-   N-(3,5-Dichloropyridin-4-yl)-4-(difluoromethoxy)-3-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)propoxy)benzamide    B83. ¹H NMR (400 MHz, DMSO-d₆) δ 11.01 (s, 1H), 10.69 (s, 1H), 8.77    (s, 2H), 7.77 (s, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.41-7.04 (m, 4H),    5.14 (dd, J=4.8, 13.2 Hz, 1H), 4.54-4.32 (m, 2H), 4.21 (s, 2H),    3.03-2.88 (m, 3H), 2.67-2.58 (m, 2H), 2.50-2.32 (m, 3H), 2.03-1.99    (m, 5H), 1.89-1.79 (m, 4H); MS (ESI) m/z: 734.2 [M+H]⁺.

-   3-(Cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-((9-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)nonyl)oxy)benzamide    B84. ¹H NMR (400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 10.41 (s, 1H), 9.32    (s, 1H), 8.75 (s, 2H), 7.65 (d, J=8.4 Hz, 1H), 7.44-7.41 (m, 2H),    7.31 (d, J=10.4 Hz, 1H), 7.12 (d, J=8.8 Hz, 1H), 5.17 (dd, J=4.8,    13.2 Hz, 1H), 4.75-4.71 (m, 1H), 4.55-4.35 (m, 2H), 4.06 (t, J=6.0    Hz, 2H), 3.60 (d, J=10.4 Hz, 2H), 3.08-2.90 (m, 6H), 2.65-2.61 (m,    1H), 2.46-2.32 (m, 3H), 2.09-1.93 (m, 7H), 1.83-1.76 (m, 3H),    1.67-1.61 (m, 3H), 1.47-1.45 (m, 2H), 1.36-1.33 (m, 8H); MS (ESI)    m/z: 822.3 [M+H]⁺.

-   3-((9-(4-(2-(1-Acetamido-1-oxopropan-2-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)nonyl)oxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide    B85. ¹H NMR (400 MHz, DMSO-d₆) δ 11.88 (s, 1H), 10.60 (brs, 1H),    8.75 (s, 2H), 7.72 (s, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.42-7.00 (m,    4H), 5.05 (d, J=7.2 Hz, 1H), 4.68-4.58 (m, 2H), 4.21-4.05 (m, 2H),    2.94 (d, J=8.8 Hz, 2H), 2.69-2.67 (m, 1H), 2.34-2.30 (m, 2H), 2.20    (s, 3H), 2.06-1.93 (m, 3H), 1.85-1.66 (m, 5H), 1.54-1.52 (m, 3H),    1.45-1.40 (m, 5H), 1.30-1.26 (m, 8H); MS (ESI) m/z: 820.3 [M+H]⁺.

-   (2S,4R)-1-((S)-2-(9-(2-(Cyclopropylmethoxy)-5-((3,5-dichloropyridin-4-yl)carbamoyl)phenoxy)nonanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide    B86. ¹H NMR (400 MHz, DMSO-d₆) δ 10.37 (s, 1H), 8.95 (s, 1H), 8.71    (s, 2H), 8.53 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.62 (d, J=7.6 Hz,    1H), 7.40-7.37 (m, 5H), 7.08 (d, J=8.8 Hz, 1H), 5.10 (s, 1H),    4.71-4.68 (m, 1H), 4.52 (d, J=9.2 Hz, 1H), 4.42-4.38 (m, 2H), 4.33    (s, 1H), 4.19 (dd, J=4.0 Hz, 15.6 Hz, 1H), 4.02-3.63 (m, 2H), 3.33    (s, 2H), 2.48-2.42 (m, 5H), 2.26-2.28 (m, 1H), 2.10-2.08 (m, 4H),    2.04-2.02 (m, 1H), 1.88-1.86 (m, 3H) 1.76-1.72 (m, 1H), 1.64-1.59    (m, 4H), 1.48-1.40 (m, 7H), 1.25 (s, 9H); MS (ESI) m/z: 924.2    [M+H]⁺.

-   5-(3-(Cyclopentyloxy)-4-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)oxy)phenyl)-4H-thieno[2,3-c]pyrrole-4,6(5H)-dione    B87. ¹H NMR (400 MHz, DMSO-d₆) δ 10.99 (s, 1H), 8.28 (d, J=4.8 Hz,    1H), 7.55 (d, J=4.8 Hz, 1H), 7.40-7.33 (m, 2H), 7.05-7.01 (m, 2H),    6.90-6.87 (m, 1H), 5.13 (dd, J=5.2, 13.6 Hz, 1H), 4.73-4.71 (m, 1H),    4.52-4.31 (m, 2H), 3.99 (t, J=6.0 Hz, 2H), 2.99-2.91 (m, 3H),    2.62-2.58 (m, 2H), 2.45-2.42 (m, 1H), 2.31 (t, J=6.4 Hz, 2H),    2.02-1.99 (m, 3H), 1.86-1.83 (m, 2H), 1.74-1.72 (m, 10H), 1.60-1.57    (m, 2H), 1.45-1.40 (m, 4H), 1.36-1.31 (m, 4H); MS (ESI) m/z: 771.3    [M+H]⁺.

-   N-(3,5-Dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)heptyl)oxy)benzamide    B90. ¹H NMR (400 MHz, DMSO-d₆) δ 11.07 (s, 1H), 10.65 (s, 1H), 8.76    (s, 2H), 7.72 (s, 1H), 7.68-7.64 (m, 2H), 7.37-7.00 (m, 4H), 5.09    (dd, J=5.2, 12.8 Hz, 1H), 4.12 (t, J=6.4 Hz, 2H), 2.86-2.80 (m, 3H),    2.60-2.56 (m, 1H), 2.02-1.98 (m, 2H), 1.79-1.73 (m, 4H), 1.45-1.27    (m, 16H); MS (ESI) m/z: 786.2 [M+H]⁺.

-   3-(4-(1-(7-(2-(Cyclopentyloxy)-4-(4-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)phenoxy)heptyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione    B91. ¹H NMR (400 MHz, DMSO-d₆) δ 11.00 (s, 1H), 7.70 (d, J=5.2 Hz,    1H), 7.49 (d, J=2.4 Hz, 1H), 7.39 (d, J=10.4 Hz, 1H), 7.35 (d, J=7.6    Hz, 1H), 7.23 (d, J=8.8 Hz, 1H), 7.13 (dd, J=2.4, 8.8 Hz, 1H), 6.98    (d, J=8.8 Hz, 1H), 5.13 (dd, J=5.2, 13.6 Hz, 1H), 5.04 (s, 2H), 4.79    (s, 1H), 4.43-4.31 (m, 2H), 3.94 (t, J=6.0 Hz, 2H), 3.30 (s, 3H),    2.97-2.95 (m, 2H), 2.92-2.87 (m, 1H), 2.67-2.57 (m, 2H), 2.45-2.39    (m, 1H), 2.33-2.31 (m, 2H), 2.02-1.98 (m, 2H), 1.87-1.82 (m, 2H),    1.77-1.69 (m, 8H), 1.61-1.57 (m, 2H), 1.47-1.42 (m, 4H), 1.37-1.30    (m, 4H); MS (ESI) m/z: 757.4 [M+H]⁺.

The following compounds are prepared similarly according to thesynthetic procedures or methodologies exemplified herein.

-   8-(4-(2-(2,6-Dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)octanamide    B1.

-   3-(7-(4-(2-(2,6-Dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)-4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile    B5.

-   2-(7-(4-(2-(2,6-Dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)-4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile    B6.

-   3-(4-(1-(7-((4-((3,5-Dichloropyridin-4-yl)amino)-7-methoxy-2-oxo-2H-chromen-8-yl)oxy)heptyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione    B7.

-   3-(2-(2-(3-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)propoxy)-ethoxy)ethoxy)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)propanamide    B8.

-   N-(6-(2-(2-(2-(3-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)propoxy)-ethoxy)ethoxy)ethyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide    B9.

-   3-(Cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-N-(2-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)propoxy)ethoxy)ethoxy)-ethyl)benzamide    B10.

-   N-(3,5-Dichloropyridin-4-yl)-4-(difluoromethoxy)-3-(2-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)propoxy)ethoxy)ethoxy)ethoxy)benzamide    B11.

-   4-(2-(2-(2-(3-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)propoxy)-ethoxy)ethoxy)ethyl)-3-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile    B12.

-   2-(2-(2-(2-(3-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)propoxy)-ethoxy)ethoxy)ethyl)-4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile    B13.

-   3-(4-((3-(2-(2-(2-((4-((3,5-Dichloropyridin-4-yl)amino)-7-methoxy-2-oxo-2H-chromen-8-yl)oxy)ethoxy)ethoxy)ethoxy)propyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione    B14.

-   6-(4-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidin-1-yl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)-6-oxohexanamide    B15.

-   3-(Cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-N-(5-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidin-1-yl)-5-oxopentyl)benzamide    B17.

-   4-(5-(4-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidin-1-yl)-5-oxopentyl)-3-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile    B19.

-   2-(5-(4-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidin-1-yl)-5-oxopentyl)-4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile    B20.

-   3-(4-((1-(5-((4-((3,5-Dichloropyridin-4-yl)amino)-7-methoxy-2-oxo-2H-chromen-8-yl)oxy)pentanoyl)piperidin-4-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione    B21.

-   8-(4-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)piperidin-1-yl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)octanamide    B22.

-   N-(6-(7-(4-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide    B23.

-   3-(Cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-N-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)benzamide    B24.

-   N-(3,5-Dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)oxy)benzamide    B25.

-   3-(7-(4-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)-4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile    B26.

-   2-(7-(4-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)-4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile    B27.

-   3-(4-(1-(7-((4-((3,5-Dichloropyridin-4-yl)amino)-7-methoxy-2-oxo-2H-chromen-8-yl)oxy)heptyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione    B28.

-   8-(4-((5-(2,6-Dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)phenyl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)octanamide    B29.

-   N-(6-(7-(4-((5-(2,6-Dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)phenyl)heptyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide    B30.

-   3-(Cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-N-(7-(4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)phenyl)-heptyl)benzamide    B31.

-   N-(3,5-Dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-(4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)phenyl)heptyl)oxy)benzamide    B32.

-   3-(7-(4-((5-(2,6-Dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)phenyl)heptyl)-4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile    B33.

-   2-(7-(4-((5-(2,6-Dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)phenyl)heptyl)-4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile    B34.

-   3-(1-((4-(7-((4-((3,5-Dichloropyridin-4-yl)amino)-7-methoxy-2-oxo-2H-chromen-8-yl)oxy)heptyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione    B35.

-   (2S,4R)-1-((S)-2-((8-((2-((S)-1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethyl)-1,3-dioxoisoindolin-4-yl)amino)-8-oxooctyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide    B36.

-   (2S,4R)-1-((S)-2-((7-(7-Acetamido-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-5-yl)heptyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide    B37.

-   (2S,4R)-1-((S)-2-((7-(3-(Cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamido)heptyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide    B38.

-   (2S,4R)-1-((S)-2-((7-(5-((3,5-Dichloropyridin-4-yl)carbamoyl)-2-(difluoromethoxy)-phenoxy)heptyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)-pyrrolidine-2-carboxamide    B39.

-   (2S,4R)-1-((S)-2-((7-(5-Cyano-2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)phenyl)heptyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide    B40.

-   (2S,4R)-1-((S)-2-((7-(3-Cyano-5-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)phenyl)heptyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide    B41.

-   (2S,4R)-1-((S)-2-((7-((4-((3,5-Dichloropyridin-4-yl)amino)-7-methoxy-2-oxo-2H-chromen-8-yl)oxy)heptyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide    B42.

Example B1. Cell-based TNF-α Inhibition Assay

Frozen primary blood mononuclear cells (PBMCs) were quick thawed, washedonce with RPMI 1640 media supplemented with 10% fetal bovine serum, 1%penicillin, and 1% streptomycin, and plated in a 96 well plate at200,000 cells per well. The cells were pretreated with DMSO only as acontrol or a compound for 1 h, and then induced with LPS(lipopolysaccharide) (100 ng/mL) for 18-24 h. The supernatant wasanalyzed for TNF-α using the Meso Scale assay. Compound activity wasdetermined as a percentage of the stimulated DMSO control. The resultsare summarized in Table 1, where A represents a percent inhibitionvalue≥60%; B represents a percent inhibition value<60% and ≥40%; Crepresents a percent inhibition value<40% and >20%; and D represents asingle percent inhibition value<20%.

TABLE 1 TNF-α Inhibition Compound Concentration Compound No. 0.1 μM 1 μMA1  D B A2  C C A3  C C A4  B A A5  D C A6  D C A7  D D A8  D D A9  B AA10 D A A11 C A B2  A B3  D D B4  A A B16 A A B18 A A B43 A A B44 A B45A B46 A B47 A B48 A B49 D B50 D B51 C B52 D B53 D B54 C B55 C B56 B B57D B58 D B59 D B60 C B61 A A B62 D B63 A A B64 A A B65 D B66 A B67 A B68A A B69 B A B70 A A B71 A A B72 A A B73 A A B74 A A B75 A A B76 A A B77B A B78 A B79 A A B80 A B82 A A B83 C B84 A B85 C B86 A B87 D

Example B2. Protein Degradation Assay

A549 cells were grown in RPMI 1640 media supplemented with 10% fetalbovine serum, streptomycin, and penicillin. The cells were plated in6-well plates in the growth media. The next day, fresh growth media werereplaced on the cells. The cells were then treated with a compound for24 h at predetermined concentrations. Whole cell extracts were preparedusing an immunoprecipitation (IP) lysis buffer. Briefly, the cells werewashed once in PBS, and the cell pellets were resuspended in the IPlysis buffer and incubated for 15 min on ice. Cells debris was removedby centrifugation and the cleared whole cell lysates were transferred tonew tubes for further analysis.

For a western blot analysis, the whole cell protein extracts wereseparated on 4-12% SDS-polyacrylamide gels, transferred tonitrocellulose, and probed with primary antibodies. Membranes weresubsequently washed and probed with IRDYE® secondary antibodies. Thesignals were detected using an ODYSSEY® Imaging System. The antibodiesused in the assay included anti-PDE4B antibody; anti-PDE4D antibodies(top, bottom, and short isoform); β-actin mouse monoclonal antibody;IRDYE® 680RD goat anti-rabbit antibody; and IRDYE® 800CW goat anti-mouseantibody. Compounds B2 to B4, B18, B49 to B52, B76, B77, B79, B81 toB83, B88, B89, and B91 were determined to be able to degradate PDE4B ashigh as about 50% relative to DMSO. Compounds B2 to B4, B16, B18, B43,B44, B47, B51, B52, B54, B58, B70, B74 to B79, B88, and B89 weredetermined to be able to degradate PDE4D, in particular, PDE4D shortisoform, as high as about 95% relative to DMSO; whereas apremilast didnot degradate the PDE4D under the same conditions.

*****

The examples set forth above are provided to give those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the claimed embodiments and are not intended to limit thescope of what is disclosed herein. Modifications that are obvious topersons of skill in the art are intended to be within the scope of thefollowing claims. All publications, patents, and patent applicationscited in this specification are incorporated herein by reference as ifeach such publication, patent or patent application were specificallyand individually indicated to be incorporated herein by reference.

What is claimed is:
 1. A compound of Formula (II):R^(W)-L²-X-L¹-R¹(II) or an enantiomer, a mixture of enantiomers, adiastereomer, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;wherein: R¹ is

R^(W) is

X is C₁-C₁₅ alkylene, heteroalkylene, C₂-C₁₀ alkenylene, C₂-C₁₀alkynylene, phenylene, five to six membered heteroarylene, three to sixmembered heterocyclylene, or C₃-C₈ cycloalkylene, wherein each ofphenylene, five to six membered heteroarylene, three to six memberedheterocyclylene, or C₃-C₈ cycloalkylene is optionally substituted withone or more R¹⁸; or X is C₁-C₁₅ alkylene, heteroalkylene, C₂-C₁₀alkenylene, or C₂-C₁₀ alkynylene, wherein one or more methylenerepeating units is replaced by a ring structure selected from the groupconsisting of phenylene, five to six membered heteroarylene, three tosix membered heterocyclylene, or C₃-C₈ cycloalkylene, and wherein eachring structure is optionally substituted with one or more R¹⁸; each Y isindependently CH₂, O, S, or NH; L¹ is a bond,

L² is a bond, —O—, —S—, —NR^(16a)—, —(CH₂)₁₋₃—, —C(═O)—, or—(CH₂)₀₋₃C(═O)NR^(16a)—; each Q is independently CH₂ or C(═O); each ofQ¹, Q², and Q³ is independently S or CH, provided that one of Q¹, Q²,and Q³ is S; each R^(A) is independently halogen, deuterium, hydroxyl,cyano, nitro, optionally substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, optionallysubstituted amino, C₁-C₆ alkylamino, (amino)C₁-C₆ alkyl,—(C═O)NR^(17a)R^(17b), (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O—(C₁-C₆ alkoxy)C₁-C₆alkyl, or optionally substituted C₃-C₇ cycloalkyl; and R^(B) is H orR^(A); each of R², R^(2a) and R^(2b) is independently H, deuterium,halogen, or C₁-C₆ alkyl; each R^(2c) is independently H, C₁-C₆ alkyl, orC₃-C₈ cycloalkyl, wherein the C₃-C₈ cycloalkyl is optionally substitutedwith C₁-C₆ alkyl, halogen, or C₁-C₆ haloalkyl; each R^(2d) isindependently H, OH, halogen, —O—C₁-C₆ alkyl, —O—C₁-C₆ haloalkyl, or—O—C₃-C₈ cycloalkyl, wherein —O—C₃-C₈ cycloalkyl is optionallysubstituted with C₁-C₆ alkyl, halogen, or C₁-C₆ haloalkyl; each R^(2e)is independently —C(═O)—C₁-C₆ alkyl or —C(═O)—C₃-C₈ cycloalkyl, eachoptionally substituted with one or more substituents, each of which isindependently selected from the group consisting of cyano, halogen,hydroxyl, amino, and C₁-C₆ haloalkyl; each R³ is independently H,deuterium, C₁-C₆ alkyl,

each R⁴ is independently —NR^(4A)R^(4B), —NR^(4A)C(═O)R^(4C),—NR^(4A)SO₂R^(4C), or —N(C(═O)R^(4A))(C(═O)R^(4C)); each of R^(4A) andR^(4B) is independently H, optionally substituted C₁-C₆ alkyl, C₁-C₆haloalkyl, (C₁-C₆ alkoxy)C₁-C₆ alkyl, optionally substituted C₃-C₇cycloalkyl, optionally substituted 3 to 10 membered heterocyclyl,optionally substituted C₆-C₁₀ aryl, optionally substituted C₇-C₁₄aralkyl, or optionally substituted 5 to 10 membered heteroaryl; eachR^(4C) is independently C₁-C₆ alkyl, C₁-C₆ haloalkyl, (C₁-C₆alkoxy)C₁-C₆ alkyl, optionally substituted C₃-C₇ cycloalkyl, optionallysubstituted (C₃-C₇ cycloalkyl)C₁-C₆ alkyl, optionally substituted 3 to10 membered heterocyclyl, optionally substituted (3 to 10 memberedheterocyclyl)C₁-C₆ alkyl, optionally substituted C₆-C₁₀ aryl, optionallysubstituted C₇-C₁₄ aralkyl, optionally substituted 5 to 10 memberedheteroaryl, or (optionally substituted 5 to 10 membered heteroaryl)C₁-C₆alkyl; each R⁵ is independently H, deuterium, halogen, or optionallysubstituted C₁-C₆ alkyl; each R⁶ is independently C₁-C₆ alkyl, hydroxyl,—NR^(4A)R^(4B), optionally substituted C₃-C₇ cycloalkyl, optionallysubstituted 3 to 10 membered heterocyclyl, optionally substituted C₆-C₁₀aryl, or optionally substituted 5 to 10 membered heteroaryl; each of R⁷,R¹⁰, and R¹¹ is independently H, deuterium, halogen, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, optionally substituted C₃-C₇cycloalkyl, optionally substituted 3 to 10 membered heterocyclyl,optionally substituted C₆-C₁₀ aryl, or optionally substituted 5 to 10membered heteroaryl; each of R⁸ and R⁹ is independently optionallysubstituted C₁-C₆ alkyl, C₁-C₆ haloalkyl, optionally substituted C₃-C₇cycloalkyl, optionally substituted (C₃-C₇ cycloalkyl)C₁-C₆ alkyl,optionally substituted 3 to 10 membered heterocyclyl, optionallysubstituted (3 to 10 membered heterocyclyl)C₁-C₆ alkyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₇-C₁₄ aralkyl,optionally substituted 5 to 10 membered heteroaryl, or (optionallysubstituted 5 to 10 membered heteroaryl)C₁-C₆ alkyl; each R¹² isindependently H or deuterium; each of R¹³ and R¹⁴ is independentlyhalogen, hydroxyl, cyano, nitro, optionally substituted C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, optionally substitutedamino, (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O—(C₁-C₆ alkoxy)C₁-C₆ alkyl, oroptionally substituted C₃-C₇ cycloalkyl; each of R¹⁵, R¹⁶, R^(16a), andR^(16b) is independently H or C₁-C₆ alkyl; each R^(17a) and R^(17b) isindependently H or C₁-C₆ alkyl, or R^(17a) and R^(17b) together with thenitrogen atom to which they are attached form 5 or 6 memberedheterocyclyl, each optionally substituted with one or more R¹⁸; each R¹⁸is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O—(C₁-C₆ alkoxy)C₁-C₆ alkyl,optionally substituted amino, halogen, or cyano; or two geminal R¹⁸ formoxo; each of R^(19a) and R^(19b) is independently H, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl,optionally substituted C₂-C₆ alkynyl, optionally substituted C₆-C₁₀aryl, optionally substituted 5 to 10 membered heteroaryl, optionallysubstituted C₇-C₁₄ aralkyl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted C₃-C₈ carbocyclyl; each ofR^(20a) and R^(20b) is independently H, halogen, C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or C₃-C₈ carbocyclyl; each ofR^(21a) and R^(21b) is independently H, optionally substituted C₁-C₆alkyl, optionally substituted C₆-C₁₀ aryl, optionally substituted C₇-C₁₄aralkyl, or optionally substituted C₃-C₈ carbocyclyl; each of X¹ and X²is independently O or S; each Z¹ is independently a bond,—(CR^(a)R^(b))_(q1)—, —C(═O)—, —CH═CH—, or —C≡C—; each Z² isindependently —(CR^(c)R^(d))_(q2)—; each of Z³ and Z⁴ is independentlyNR¹⁶, O, S, or a bond; each of R^(a), R^(b), R^(c), and R^(d) isindependently H, halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, or optionally substituted C₃-C₆ cycloalkyl;each Ring A is independently phenylene, five to six memberedheteroarylene, three to six membered heterocyclylene, or C₃-C₈cycloalkylene, each optionally substituted with one or more R¹⁸; each ofm1, m2, m3, m4, m5, m6, m7, m8, m9, k1, k2, k3, k4, k5, k6, k7, k8, andk9 is independently an integer of 0, 1, 2, 3, 4, or 5; each n isindependently an integer of 0, 1, or 2; and each q1 and q2 isindependently an integer of 1, 2, or
 3. 2. The compound of claim 1,wherein R¹ is


3. The compound of claim 1 or 2, wherein R^(W) is


4. The compound of claim 1 or 3, having the structure of Formula (III):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 5. The compoundof claim 1, 3, or 4, wherein n is an integer of
 1. 6. The compound ofany one of claims 1 and 3 to 5, wherein Q¹ is S.
 7. The compound of anyone of claims 1 and 3 to 5, wherein Q² is S.
 8. The compound of any oneof claims 1 and 3 to 5, wherein Q³ is S.
 9. The compound of any one ofclaims 1 to 5 and 7, having the structure of Formula (IV):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 10. The compoundof claim 1 or 3, having the structure of Formula (XV):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 11. The compoundof claim 1, 3, or 10, having the structure of Formula (XVI):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 12. The compoundof claim 1, 3, or 10, having the structure of Formula (XXVII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 13. The compoundof any one of claims 1 to 12, wherein each Q is CH₂.
 14. The compound ofany one of claims 1 to 12, wherein each Q is C(═O).
 15. The compound ofany one of claims 1 to 12, wherein one of the two Q group is CH₂ and theother is C(═O).
 16. The compound of claim 1, 9, or 15, having thestructure of Formula (V):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 17. The compoundof claim 16, having the structure of Formula (VII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 18. The compoundof claim 16 or 17, having the structure of Formula (VIII):

or a diastereomer, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.19. The compound of claim 11 or 15, having the structure of Formula(XVII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 20. The compoundof claim 19, having the structure of Formula (XIX):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 21. The compoundof claim 19 or 20, having the structure of Formula (XX):

or a diastereomer, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.22. The compound of claim 12 or 15, having the structure of Formula(XXVIII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 23. The compoundof claim 22, having the structure of Formula (XXX):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 24. The compoundof claim 22 or 23, having the structure of Formula (XXXI):

or a diastereomer, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.25. The compound of claim 1 or 2, wherein R^(W) is


26. The compound of claim 1 or 25, having the structure of Formula (IX):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 27. The compoundof claim 26, wherein n is an integer of
 1. 28. The compound of claim 26or 27, wherein Q¹ is S.
 29. The compound of claim 26 or 27, wherein Q²is S.
 30. The compound of claim 26 or 27, wherein Q³ is S.
 31. Thecompound of claim 1, 25, 26, or 29, having the structure of Formula (X):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 32. The compoundof claim 1 or 25, having the structure of Formula (XXI):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 33. The compoundof claim 32, having the structure of Formula (XXII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 34. The compoundof claim 1 or 25, having the structure of Formula (XXXII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 35. The compoundof claim 34, having the structure of Formula (XXXIII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 36. The compoundof any one of claims 25 to 35, wherein each Q is CH₂.
 37. The compoundof any one of claims 25 to 35, wherein each Q is C(═O).
 38. The compoundof any one of claims 25 to 35, wherein one of the two Q group is CH₂ andthe other is C(═O).
 39. The compound of any one of claims 31 or 38,having the structure of Formula (XI):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 40. The compoundof claim 39, having the structure of Formula (XIII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 41. The compoundof claim 39 or 40, having the structure of Formula (XIV):

or a diastereomer, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.42. The compound of claim 33 or 38, having the structure of Formula(XXIII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 43. The compoundof claim 42, having the structure of Formula (XXV):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 44. The compoundof claim 42 or 43, having the structure of Formula (XXVI):

or a diastereomer, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.45. The compound of claim 35 or 38, having the structure of Formula(XXXIV):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 46. The compoundof claim 45, having the structure of Formula (XXXVI):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 47. The compoundof claim 45 or 46, having the structure of Formula (XXXVII):

or a diastereomer, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.48. The compound of any one of claims 11 to 15, 19 to 24, 32 to 38, and42 to 47, wherein R^(B) is H or halo.
 49. The compound of claim 48,wherein R^(B) is H or fluoro.
 50. The compound of claim 1, having thestructure of Formula (XXXVIII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 51. The compoundof claim 50, having the structure of Formula (XL):

or a diastereomer, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.52. The compound of claim 1, having the structure of Formula (XLI):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 53. The compoundof claim 52, having the structure of Formula (XLII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 54. The compoundof claim 52 or 53, having the structure of Formula (XLIV):

or a diastereomer, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.55. The compound of any one of claims 1 to 54, wherein R⁶ is optionallysubstituted C₁-C₆ alkyl or optionally substituted C₃-C₇ cycloalkyl. 56.The compound of any one of claims 1 to 55, wherein R⁶ is optionallysubstituted C₁-C₆ alkyl.
 57. The compound of any one of claims 1 to 56,wherein R⁶ is methyl.
 58. The compound of any one of claims 1 to 57,wherein R⁸ is optionally substituted C₁-C₆ alkyl or optionallysubstituted C₃-C₇ cycloalkyl.
 59. The compound of any one of claims 1 to58, wherein R⁸ is optionally substituted C₁-C₆ alkyl.
 60. The compoundof any one of claims 1 to 59, wherein R⁸ is ethyl.
 61. The compound ofany one of claims 1 to 60, wherein R⁹ is optionally substituted C₁-C₆alkyl or optionally substituted C₃-C₇ cycloalkyl.
 62. The compound ofany one of claims 1 to 61, wherein R⁹ is optionally substituted C₁-C₆alkyl.
 63. The compound of any one of claims 1 to 62, wherein R⁹ ismethyl.
 64. The compound of claim 1 or 2, wherein R^(W) is


65. The compound of claim 1 or 64, having the structure of Formula(XLV):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 66. The compoundof claim 65, having the structure of Formula (XLVI):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 67. The compoundof claim 1 or 64, having the structure of Formula (XLIX):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 68. The compoundof claim 67, having the structure of Formula (L):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 69. The compoundof claim 1, 2, or 64, having the structure of Formula (LIII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 70. The compoundof claim 69, having the structure of Formula (LIV):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R^(B) isH, halogen, or optionally substituted C₁-C₆ alkyl.
 71. The compound ofclaim 69, having the structure of Formula (LVII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R^(B) isH, halogen, or optionally substituted C₁-C₆ alkyl.
 72. The compound ofclaim 1, 2, or 64, having the structure of Formula (LX):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R^(B) isH, halogen, or optionally substituted C₁-C₆ alkyl.
 73. The compound ofclaim 72, having the structure of Formula (LXI):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R^(B) isH, halogen, or optionally substituted C₁-C₆ alkyl.
 74. The compound ofclaim 72, having the structure of Formula (LXIV):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R^(B) isH, halogen, or optionally substituted C₁-C₆ alkyl.
 75. The compound ofany one of claims 1, 2, and 64 to 74, wherein Q is CH₂.
 76. The compoundof any one of claims 1, 2, and 64 to 74, wherein Q is C(═O).
 77. Thecompound of any one of claims 1, 2, and 64 to 76, wherein R² is H. 78.The compound of any one of claims 1, 2, and 64 to 77, wherein R³ is H.79. The compound of any one of claims 1, 2, and 64 to 78, wherein R^(B)is H or halo.
 80. The compound of any one of claims 1, 2, and 64 to 79,wherein R^(B) is H or fluoro.
 81. The compound of claim 1 or 64, havingthe structure of Formula (LXVII):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 82. The compoundof claim 1 or 64, having the structure of Formula (LXX):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 83. The compoundof any one of claims 1, 2, and 64 to 82, wherein R⁷ is H or deuterium.84. The compound of any one of claims 1, 2, 64, 67, 68, 72 to 80, and 82to 83, wherein R⁸ is optionally substituted C₁-C₆ alkyl, C₁-C₆haloalkyl, or optionally substituted (C₃-C₇ cycloalkyl)C₁-C₆ alkyl. 85.The compound of any one of claims 1, 2, 64, 67, 68, 72 to 80, and 82 to84, wherein R⁸ is methyl, difluoromethyl, trifluoromethyl, orcyclopropylmethyl.
 86. The compound of any one of claims 1, 2, 64 to 66,69, 70, 71, 75 to 81, and 83, wherein R⁹ is optionally substituted C₁-C₆alkyl, C₁-C₆ haloalkyl, or optionally substituted (C₃-C₇cycloalkyl)C₁-C₆ alkyl.
 87. The compound of any one of claims 1, 2, 64to 66, 69, 70, 71, 75 to 81, 83, and 86, wherein R⁹ is methyl,difluoromethyl, trifluoromethyl, or cyclopropylmethyl.
 88. The compoundof any one of claims 1, 2, and 64 to 87, wherein R¹⁰ is H or deuterium.89. The compound of any one of claims 1, 2, and 64 to 88, wherein R¹¹ isH or deuterium.
 90. The compound of any one of claims 1, 2, and 64 to89, wherein R¹³ is halogen, or optionally substituted C₁-C₆ alkyl. 91.The compound of any one of claims 1, 2, and 64 to 90, wherein R¹³ ischloro.
 92. The compound of any one of claims 1, 2, and 64 to 91,wherein R¹⁴ is halogen, or optionally substituted C₁-C₆ alkyl.
 93. Thecompound of any one of claims 1, 2, and 64 to 92, wherein R¹⁴ is chloro.94. The compound of any one of claims 1, 2, and 63 to 93, whereinR^(16b) is H.
 95. The compound of claim 1 or 2, wherein R^(W) is


96. The compound of claim 1 or 2, wherein R^(W) is


97. The compound of claim 1 or 2, wherein R^(W)


98. The compound of claim 1, 2, or 67, wherein R^(W) is


99. The compound of any one of claims 1 to 16, 19, 22, 25 to 39, 42, 45,and 48 to 98, wherein L¹ is a bond,


100. The compound of any one of claims 1 to 16, 19, 22, 25 to 39, 42,45, and 48 to 99, wherein L¹ is a bond, —NH—, pyrrolidin-1,3-diyl,piperidin-1,3-diyl, piperidin-1,4-diyl,


101. The compound of any one of claims 1 to 16, 19, 22, 25 to 39, 42,45, and 48 to 100, wherein L¹ is a bond, —NH—, piperidin-1,4-diyl,


102. The compound of any one of claims 1 to 101, wherein L² is a bond,—O—, —NR^(16a)—, —(CH₂)₁₋₃—, —C(═O)—, or —(CH₂)₀₋₃C(═O)NR^(16a)—. 103.The compound of any one of claims 1 to 102, wherein L² is a bond, —O—,—NH—, or —C(═O)NH—.
 104. The compound of any one of claims 1 to 103,wherein X is C₁-C₁₅ alkylene or heteroalkylene.
 105. The compound of anyone of claims 1 to 104, wherein X is C₁-C₁₅ alkylene or heteroalkylene,where one or more methylene repeating units is replaced by a ringstructure, each ring structure independently selected from the groupconsisting of phenylene, five to six membered heteroarylene, five to sixmembered heterocyclylene, and C₃-C₈ cycloalkylene.
 106. The compound ofany one of claims 1 to 105, wherein X is propan-1,3-diyl,butan-1,4-diyl, pentan-1,5-diyl, hexan-1,6-diyl, heptan-1,7-diyl,octan-1,8-diyl, nonan-1,9-diyl, decan-1,10-diyl, undecan-1,11-diyl,dodecan-1,12-diyl, hept-1-yn-1,7-diyl,


107. The compound of claim 1, wherein the compound is8-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)octanamideB1;N-(6-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamideB2;3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-N-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)benzamideB3;N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)oxy)benzamideB4;3-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)-4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrileB5;2-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)-4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrileB6;3-(4-(1-(7-((4-((3,5-dichloropyridin-4-yl)amino)-7-methoxy-2-oxo-2H-chromen-8-yl)oxy)heptyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dioneB7;3-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)propoxy)-ethoxy)ethoxy)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)propanamideB8;N-(6-(2-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)propoxy)-ethoxy)ethoxy)ethyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamideB9;3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-N-(2-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)propoxy)ethoxy)ethoxy)-ethyl)benzamideB10;N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-(2-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)propoxy)ethoxy)ethoxy)ethoxy)benzamideB11;4-(2-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)propoxy)-ethoxy)ethoxy)ethyl)-3-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrileB12;2-(2-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)propoxy)-ethoxy)ethoxy)ethyl)-4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrileB13;3-(4-((3-(2-(2-(2-((4-((3,5-dichloropyridin-4-yl)amino)-7-methoxy-2-oxo-2H-chromen-8-yl)oxy)ethoxy)ethoxy)ethoxy)propyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneB14;6-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidin-1-yl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)-6-oxohexanamideB15;N-(6-(5-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidin-1-yl)-5-oxopentyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamideB16;3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-N-(5-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidin-1-yl)-5-oxopentyl)benzamideB17;N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((5-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidin-1-yl)-5-oxopentyl)oxy)benzamideB18;4-(5-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidin-1-yl)-5-oxopentyl)-3-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrileB19;2-(5-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidin-1-yl)-5-oxopentyl)-4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrileB20;3-(4-((1-(5-((4-((3,5-dichloropyridin-4-yl)amino)-7-methoxy-2-oxo-2H-chromen-8-yl)oxy)pentanoyl)piperidin-4-yl)ethynyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneB21;8-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)piperidin-1-yl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)octanamideB22;N-(6-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamideB23;3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-N-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)benzamideB24;N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)oxy)benzamideB25;3-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)-4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrileB26;2-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)-4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrileB27;3-(4-(1-(7-((4-((3,5-dichloropyridin-4-yl)amino)-7-methoxy-2-oxo-2H-chromen-8-yl)oxy)heptyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneB28;8-(4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)phenyl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)octanamideB29;N-(6-(7-(4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)phenyl)heptyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamideB30;3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-N-(7-(4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)phenyl)-heptyl)benzamideB31;N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-(4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)phenyl)heptyl)oxy)benzamideB32;3-(7-(4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)phenyl)heptyl)-4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrileB33;2-(7-(4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)phenyl)heptyl)-4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrileB34;3-(1-((4-(7-((4-((3,5-dichloropyridin-4-yl)amino)-7-methoxy-2-oxo-2H-chromen-8-yl)oxy)heptyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dioneB35;(2S,4R)-1-((S)-2-((8-((2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)-ethyl)-1,3-dioxoisoindolin-4-yl)amino)-8-oxooctyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamideB36;(2S,4R)-1-((S)-2-((7-(7-acetamido-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-5-yl)heptyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamideB37;(2S,4R)-1-((S)-2-((7-(3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamido)heptyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamideB38;(2S,4R)-1-((S)-2-((7-(5-((3,5-dichloropyridin-4-yl)carbamoyl)-2-(difluoromethoxy)-phenoxy)heptyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)-pyrrolidine-2-carboxamideB39;(2S,4R)-1-((S)-2-((7-(5-cyano-2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)phenyl)heptyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamideB40;(2S,4R)-1-((S)-2-((7-(3-cyano-5-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)phenyl)heptyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamideB41;(2S,4R)-1-((S)-2-((7-((4-((3,5-dichloropyridin-4-yl)amino)-7-methoxy-2-oxo-2H-chromen-8-yl)oxy)heptyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamideB42;3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)-ethoxy)ethoxy)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)propanamideB43;7-((4-((5-((S)-2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)benzyl)amino)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)heptanamideB44;N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((9-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)nonyl)oxy)benzamideB45;N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((5-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)pentyl)oxy)benzamideB46;N-(6-(7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)hept-1-yn-1-yl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamideB47;14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)-3,6,9,12-tetraoxatetradecan-1-amideB48;3-(6-fluoro-4-(1-(7-(2-methoxy-5-(1-oxoisoindolin-2-yl)phenoxy)heptyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneB49;3-(4-(1-(7-(2-(cyclopentyloxy)-4-(1-oxoisoindolin-2-yl)phenoxy)heptyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dioneB50;2-(3-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)oxy)-4-methoxyphenyl)isoindoline-1,3-dioneB51;5-amino-2-(3-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)oxy)-4-methoxyphenyl)isoindoline-1,3-dioneB52;3-(6-fluoro-4-(1-(7-(2-methoxy-5-(5-oxopyrrolidin-3-yl)phenoxy)heptyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneB53;2-(3-(cyclopentyloxy)-4-methoxyphenyl)-5-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)amino)isoindoline-1,3-dioneB54;3-(6-fluoro-5-(1-(7-(2-methoxy-5-(5-oxopyrrolidin-3-yl)phenoxy)heptyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneB55;3-(4-(1-(7-((2-(3-(cyclopentyloxy)-4-methoxyphenyl)-3-oxoisoindolin-5-yl)amino)heptyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dioneB56;3-(4-(1-(7-(2-(cyclopentyloxy)-4-(5-oxopyrrolidin-3-yl)phenoxy)heptyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dioneB57;5-amino-2-(3-(cyclopentyloxy)-4-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)oxy)phenyl)isoindoline-1,3-dioneB58;2-(3-(cyclopentyloxy)-4-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)oxy)phenyl)isoindoline-1,3-dioneB59;3-(4-(1-(7-(5-(6-amino-1-oxoisoindolin-2-yl)-2-methoxyphenoxy)heptyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dioneB60;N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperidin-1-yl)heptyl)oxy)benzamideB61;3-(4-(1-(7-(5-(6-amino-1-oxoisoindolin-2-yl)-2-methoxyphenoxy)heptyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dioneB62;N¹-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)-N¹⁰-((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)decanediamideB63;3-((4-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)-methyl)benzyl)oxy)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)propanamideB64;5-(3-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)oxy)-4-methoxyphenyl)-4H-thieno[2,3-c]pyrrole-4,6(5H)-dioneB65;2-(2,6-dioxopiperidin-3-yl)-4-((7-(2-methoxy-5-(5-oxopyrrolidin-3-yl)phenoxy)-heptyl)amino)isoindoline-1,3-dioneB66;(2S,4R)-4-hydroxy-1-((2S)-2-(9-(2-methoxy-5-(5-oxopyrrolidin-3-yl)phenoxy)-nonanamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamideB67;(2S,4R)-1-((S)-2-(9-(5-((3,5-dichloropyridin-4-yl)carbamoyl)-2-(difluoromethoxy)phenoxy)nonanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamideB68;N-(6-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)propyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamideB69;9-((4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)benzyl)amino)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)nonanamideB70;12-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)dodecanamideB71;N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptyl)oxy)benzamideB72;N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((12-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)dodecyl)oxy)benzamideB73;N-(3,5-dichloropyridin-4-yl)-3-(difluoromethoxy)-4-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)ethoxy)benzamideB74;9-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-5-yl)piperidin-1-yl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)nonanamideB75;(2S,4R)-1-((S)-2-(11-(5-((3,5-dichloropyridin-4-yl)carbamoyl)-2-(difluoromethoxy)-phenoxy)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamideB76;9-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)nonanamideB77;5-((4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)benzyl)amino)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)pentanamideB78;N-(6-(12-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)dodecyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamideB79;3-(6-fluoro-4-(1-(7-(2-methoxy-5-(4-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)phenoxy)heptyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneB80;3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(2-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)propoxy)ethoxy)ethoxy)ethoxy)benzamideB81;3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)oxy)benzamideB82;N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)propoxy)benzamideB83;3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-((9-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)nonyl)oxy)benzamideB84;3-((9-(4-(2-(1-acetamido-1-oxopropan-2-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)nonyl)oxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamideB85;(2S,4R)-1-((S)-2-(9-(2-(cyclopropylmethoxy)-5-((3,5-dichloropyridin-4-yl)carbamoyl)phenoxy)nonanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamideB86;5-(3-(cyclopentyloxy)-4-((7-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)piperidin-1-yl)heptyl)oxy)phenyl)-4H-thieno[2,3-c]pyrrole-4,6(5H)-dioneB87;N-(6-(7-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)heptyl)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamideB88;3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)-N-(2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)propanamideB89;N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)heptyl)oxy)benzamideB90;3-(4-(1-(7-(2-(cyclopentyloxy)-4-(4-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)phenoxy)heptyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dioneB91; orN-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-((7-((4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methoxy)benzyl)amino)heptyl)oxy)benzamideB92; or an enantiomer, a mixture of enantiomers, a diastereomer, amixture of two or more diastereomers, a tautomer, a mixture of two ormore tautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 108. A compoundof Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R^(Het) is

each of X and X¹ is independently CH₂, C═O, SO, SO₂, or CH₂C(═O); each Yis independently H, deuterium, halogen, or optionally substituted C₁-C₆alkyl; each R¹ is independently deuterium, hydroxyl, halogen, nitro,cyano, —NR⁹R¹⁰, —NR⁹C(═O)R¹¹, —NR⁹SO₂R¹¹, —N(C(═O)R⁹)(C(═O)R¹¹),optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆ alkoxy,optionally substituted C₃-C₇ cycloalkyl, optionally substituted 3 to 10membered heterocyclyl, optionally substituted C₆-C₁₀ aryl, or optionallysubstituted 5 to 10 membered heteroaryl; R² is hydroxyl, —NR⁹R¹⁰,optionally substituted C₁-C₆ alkyl, optionally substituted C₃-C₇cycloalkyl, optionally substituted 3 to 10 membered heterocyclyl,optionally substituted C₆-C₁₀ aryl, or optionally substituted 5 to 10membered heteroaryl; each of R³, R⁶, and R⁷ is independently H,deuterium, halogen, optionally substituted C₁-C₆ alkyl, C₁-C₆ haloalkyl,optionally substituted C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, optionallysubstituted C₃-C₇ cycloalkyl, optionally substituted 3 to 10 memberedheterocyclyl, optionally substituted C₆-C₁₀ aryl, or optionallysubstituted 5 to 10 membered heteroaryl; each of R⁴ and R⁵ isindependently optionally substituted C₁-C₆ alkyl, optionally substitutedC₃-C₇ cycloalkyl, optionally substituted (C₃-C₇ cycloalkyl)C₁-C₆ alkyl,optionally substituted 3 to 10 membered heterocyclyl, optionallysubstituted (3 to 10 membered heterocyclyl)C₁-C₆ alkyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₇-C₁₄ aralkyl,optionally substituted 5 to 10 membered heteroaryl, or (optionallysubstituted 5 to 10 membered heteroaryl)C₁-C₆ alkyl; R⁸ is H ordeuterium; each of R⁹ and R¹⁰ is independently H, optionally substitutedC₁-C₆ alkyl, C₁-C₆ haloalkyl, (C₁-C₆ alkoxy)C₁-C₆ alkyl, optionallysubstituted C₃-C₇ cycloalkyl, optionally substituted 3 to 10 memberedheterocyclyl, optionally substituted C₆-C₁₀ aryl, optionally substitutedC₇-C₁₄ aralkyl, or optionally substituted 5 to 10 membered heteroaryl;and R¹¹ is optionally substituted C₁-C₆ alkyl, C₁-C₆ haloalkyl, (C₁-C₆alkoxy)C₁-C₆ alkyl, optionally substituted C₃-C₇ cycloalkyl, optionallysubstituted (C₃-C₇ cycloalkyl)C₁-C₆ alkyl, optionally substituted 3 to10 membered heterocyclyl, optionally substituted (3 to 10 memberedheterocyclyl)C₁-C₆ alkyl, optionally substituted C₆-C₁₀ aryl, optionallysubstituted C₇-C₁₄ aralkyl, optionally substituted 5 to 10 memberedheteroaryl, or (optionally substituted 5 to 10 membered heteroaryl)C₁-C₆alkyl; provided that at least one of R², R⁴, and R⁵ is optionallysubstituted C₃-C₇ cycloalkyl.
 109. A compound of:

or a pharmaceutically acceptable salt thereof.
 110. A compound of:(S)-1-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione,(S)-1-amino-5-(1-(3-cyclopropoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione,(R)-1-amino-5-(1-(3-cyclopropoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione,(S)-1-amino-5-(1-(3-cyclopropoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione,(R)-1-amino-5-(1-(3-cyclopropoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione,(S)-3-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[2,3-c]pyrrol-6(5H)-one;(S)-N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-2,2,2-trifluoroacetamideA1,(S)-N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)-2-methoxyacetamideA2,(S)-N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)cyclopropanecarboxamideA3,(S)-N-(5-(1-(3-cyclopropoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)acetamideA4,(R)-N-(5-(1-(3-cyclopropoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)acetamideA5,(S)-N-(5-(2-(cyclopropylsulfonyl)-1-(3-ethoxy-4-methoxyphenyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)acetamideA6,(S)-N-(5-(2-(cyclopropylsulfonyl)-1-(3-ethoxy-4-methoxyphenyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-2,2,2-trifluoroacetamideA7,(R)-N-(5-(2-(cyclopropylsulfonyl)-1-(3-ethoxy-4-methoxyphenyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-2,2,2-trifluoroacetamideA8,(R)-N-(5-(2-(cyclopropylsulfonyl)-1-(3-ethoxy-4-methoxyphenyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-2-methoxyacetamideA9,(R)-N-(5-(2-(cyclopropylsulfonyl)-1-(3-ethoxy-4-methoxyphenyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)acetamideA10, or(S)-N-(5-(2-(cyclopropylsulfonyl)-1-(3-ethoxy-4-methoxyphenyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-2-methoxyacetamideA11; or a pharmaceutically acceptable salt thereof.
 111. Apharmaceutical composition comprising a compound of any one of claims 1to 110, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient.
 112. A method of treating,preventing, or ameliorating one or more symptoms of a disease, disorder,or condition associated with a PDE4 in a subject, comprisingadministering to the subject in need thereof a therapeutically effectiveamount of a compound of any one of claims 1 to
 110. 113. The method ofclaim 112, wherein the disease, disorder, or condition associated with aPDE4 is an inflammatory disease.
 114. A method of treating, preventing,or ameliorating one or more symptoms of an inflammatory disease in asubject, comprising administering to the subject in need thereof atherapeutically effective amount of a compound of any one of claims 1 to110.
 115. The method of claim 113 or 114, wherein the inflammatorydisease is arthritis, ankylosing spondylitis, osteoarthritis, rheumatoidarthritis, Behcet's disease, inflammatory bowel disease, psoriasis,psoriatic arthritis, atopic dermatitis, or contact dermatitis, chronicor obstructive pulmonary disease (COPD).
 116. A method of treating,preventing, or ameliorating one or more symptoms of psoriasis, psoriaticarthritis, or atopic dermatitis in a subject, comprising administeringto the subject in need thereof a therapeutically effective amount of acompound of any one of claims 1 to
 110. 117. The method of any one ofclaims 112 to 116, wherein the compound is administered orally ortopically.
 118. The method of any one of claims 112 to 117, wherein thesubject is a human.
 119. A method of inhibiting PDE4 activity in abiological sample, comprising contacting a compound of any one of claims1 to 110, or a pharmaceutically acceptable salt thereof, with one ormore cells in the biological sample.
 120. A method of inhibiting theactivity of a phosphodiesterase 4 (PDE4), comprising contacting the PDE4with an effective amount of a compound of any one of claims 1 to 110, ora pharmaceutically acceptable salt thereof.
 121. The method of claim120, wherein the PDE4 is PDE4D.